Abstract
At mucosal surfaces, phagocytes such as macrophages coexist with microbial communities; highly controlled regulation of these interactions is essential for immune homeostasis. Pattern-recognition receptors (PRRs) are critical in recognizing and responding to microbial products, and they are subject to negative regulation through various mechanisms, including downregulation of PRR-activating components or induction of inhibitors. Insights into these regulatory mechanisms have been gained through human genetic disease–association studies, in vivo mouse studies utilizing disease models or targeted gene perturbations, and in vitro and ex vivo human cellular studies examining phagocytic cell functions. Although mouse models provide an important approach to study macrophage regulation, human and mouse macrophages exhibit differences, which must be considered when extrapolating mouse findings to human physiology. This review discusses inhibitory regulation of PRR-induced macrophage functions and the consequences of dysregulation of these functions and highlights mechanisms that have a role in intestinal macrophages and in human macrophage studies.
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Introduction
Following microbial exposure, the peripheral immune system must mount responses to limit infection and clear microbes. Mucosal surfaces, such as the intestine, continually interact with microbes1 and therefore must balance the mechanisms defending against pathogens or excessive entry of resident microbiota with mechanisms maintaining tolerance to resident microbiota. To maintain this balance, anti-microbial responses undergo tight regulation. Uncontrolled inflammation can lead to the development of autoimmune and inflammatory diseases. However, overactive inhibitory mechanisms can increase susceptibility to infections and decrease microbial clearance, which can lead to persistent inflammation. Initial microbial recognition and responses occur through innate cells, particularly phagocytes. Consistently, depleting or altering the proportion and phenotype of these cells modulates severity of multiple autoimmune and inflammatory diseases, including at mucosal surfaces.2, 3, 4, 5 Phagocytes are comprised of myeloid-derived cells such as macrophages, dendritic cells (DCs) and neutrophils;6 this review will focus on regulation in macrophages, although the regulation in DCs can be similar7 and will occasionally be highlighted.
Macrophages regulate microbes at multiple levels, including through immune mediator secretion, microbial killing, pyroptosis, adaptive immune instruction, and wound healing.6 Macrophages recognize and respond to microbial components through pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), nucleotide-binding-domain containing receptors (NLRs), retinoic-acid-inducible-gene I-like receptors, and C-type lectins.8 Distinct PRR can share specific signaling pathways but can also signal through diverse intermediates. For example, TLR2, TLR5, TLR7, and TLR9 utilize the myeloid differentiation primary response gene 88 (MyD88)-dependent pathway, which activates nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK).9 Interleukin-1 receptor (IL-1R) and IL-18R also utilize this pathway. By contrast, TLR3 signals through MyD88-independent or Toll/interleukin1-domain-containing adaptor-inducing interferon-β (TRIF) pathways.9 TLR4 utilizes both MyD88-dependent and -independent pathways.9 Although multiple PRR share pathways, the outcomes can vary dramatically.9 Contributions to this variability include different adaptor molecule combinations, subcellular PRR localization and strength of signaling; however, many mechanisms accounting for the distinct outcomes are unclear.9
PRR engagement in macrophages induces pro-inflammatory and anti-inflammatory cytokines; the balance between these cytokines influences outcomes.9 Pro- and anti-inflammatory cytokines can be distinctly regulated, as can pro-inflammatory cytokines themselves (e.g., distinct inflammasome-mediated regulation of IL-1 and IL-18 secretion). Importantly, PRR-induced cytokine regulation varies over time. For example, initial pro-inflammatory cytokine induction can be followed by anti-inflammatory cytokines and other inhibitory mechanisms, thereby contributing to inflammation resolution. Notably, altered expression of various PRR-pathway inhibitors is observed in tissue and sera in many human inflammatory diseases. However, the role of these alterations is often unknown and may be either secondary to direct dysregulation or to compensatory regulation.
Human polymorphisms in regions containing PRR-pathway genes and their regulators in macrophages have been associated with multiple autoimmune/inflammatory diseases, including inflammatory bowel disease (IBD). Polymorphisms in regions involving PRR or PRR-initiated signaling pathways (e.g., NOD2, IRF5, NFKB1, RELA, REL, RIPK2, CARD9, PTPN22), paracrine/autocrine cytokine pathways modifying PRR signaling (e.g., IL-23R, IL-12, IL-10, IL-18RAP/IL1R1, IFNGR2/IFNAR1, JAK2, STAT3, TYK2), and autophagy pathways (e.g., ATG16L1 and IRGM) are associated with IBD.10 Mouse studies provide essential mechanistic insight into how pathways in phagocytic cells mediate dysregulation in vivo; conditional ablation of pertinent genes in myeloid cells further elucidates select myeloid cell functions.7 While sharing similarities, mouse and human phagocytic cells also exhibit differences in microbial responses, cytokine induction and differentiation patterns.6, 11, 12, 13 These differences must be considered when extrapolating mouse results to human studies.12 Consequently, parallel primary human macrophage studies are necessary. This review will focus on the inhibitory mechanisms regulating phagocytic cell functions and will particularly emphasize human studies and relevance to human inflammatory diseases. Where applicable, we will highlight the relevance of such mechanisms to mucosal surfaces, particularly the intestine.
Monocyte Migration and Tissue-Dependent Differentiation
Monocytes are derived from a granulocyte monocyte-forming unit that differentiates in the bone marrow through cytokines, including monocyte-stimulating factor and granulocyte/monocyte-stimulating factor;13 the transcription factor PU.1 regulates this differentiation.13 Differentiated monocytes exit the bone marrow, enter the blood, and then migrate into tissues. In humans, circulating blood monocytes undergo apoptosis after 3–4 days,14 and must differentiate to prolong survival.15 Under homeostasis, monocytes enter tissues and become macrophages where they acquire functions integral to and characteristic of the tissues in which they reside.13 Macrophages are larger, more effective phagocytes, and survive longer than monocytes, living for up to several months.14
PRR-Induced Macrophage Functions Must be Tightly Controlled
Initial PRR-induced responses are critical in controlling microbial insults;1 however, these responses must be tightly regulated to prevent excessive cytokine secretion leading to systemic inflammatory response syndromes, including “endotoxin shock” or “sepsis,” which can result in tissue injury and death. Upon chronic microbial stimulation, PRR-induced cytokines, chemokines, and activation markers are downregulated.16, 17, 18, 19, 20 This process, termed “endotoxin tolerance”, has been most commonly described with chronic TLR4 stimulation.19 Mucosal macrophages encounter ongoing microbial exposure, and may be particularly subject to this type of regulation; multiple mechanisms contribute to reducing responsiveness to microbial products. Although some mechanisms limit acute PRR-mediated outcomes, these and other inhibitory mechanisms can be enhanced or induced following chronic microbial product stimulation. These mechanisms include downregulation of expression and/or function of PRR or critical intermediates in PRR-initiated pathways, modulation of strength of signaling, regulation by microRNAs, epigenetic regulation of gene promoters, as well as regulation by the inflammasome and autophagy (Figure 1 and Table 1). Below, we will emphasize select inhibitory mechanisms and highlight where appropriate their relevance to homeostasis at mucosal surfaces, including the intestine.
Mechanisms downregulating pattern-recognition receptor (PRR)-mediated macrophage responses. Signaling through PRR (e.g., Toll-like receptor 4 (TLR4)) activates distinct inflammatory pathways. The myeloid differentiation primary response gene 88 (MyD88)-dependent pathway signals through IRAK-1, nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways, while the MyD88-independent TRIF pathway signals through interferon regulatory factors (IRFs). Multiple mechanisms limit excessive macrophage responses induced by these pathways. They include: (1) downregulation of receptors and signaling molecules (e.g., PRRs, IRAK-1); (2) induction of decoy receptors (e.g., SIGIRR); (3) induction of intracellular or surface molecules that inhibit MyD88-dependent or -independent pathways; (4) induction of secretory molecules, including anti-inflammatory mediators (interleukin (IL)-10, transforming growth factor (TGF)-β, IL-1Ra), which suppress inflammation through multiple mechanisms; (5) signaling through alternative subunits or altering strength of signaling of molecules; (6) targeting of inflammatory RNAs by microRNAs thereby decreasing protein expression; (7) epigenetic regulation, including chromatin modification leading to inhibition of pro-inflammatory genes and/or upregulation of inhibitory genes; and (8) autophagy, which limits autocrine IL-1 secretion and therefore IL-1 contributions to secretion of additional pro-inflammatory cytokines. Inflammatory intermediates are indicated in green and inhibitory molecules/mechanisms in red. IFN, interferon; PI3K, phosphatidylinositol 3-kinase; TNF, tumor necrosis factor.
Regulating expression of PRR signaling pathway genes
PRR-initiated macrophage responses can be inhibited by downregulating the expression and/or function of PRR complexes or PRR-initiated signaling pathways (Figure 1 and Table 1). Although these mechanisms may decrease excessive inflammation and sepsis, they may also adversely affect bacterial clearance. PRR expression downregulation or receptor complex affinity alterations for microbial ligands during endotoxin tolerance have been observed in some, but not all, human and mouse macrophage studies.21, 22, 23 However, overexpressing TLR4 or TLR adaptor molecules fails to reverse downregulated cytokine secretion in certain situations,24, 25, 26 indicating that redundant endotoxin tolerance-inducing mechanisms can compensate for dysregulated modulation of receptor expression. Consistent with the requirement for TLR downregulation to limit intestinal PRR responses, epithelial cells and colitis-associated tumors from IBD patients and lamina propria macrophages from ulcerative colitis (UC) patients show increased TLR4 expression.27, 28 This may increase inflammation, as mice overexpressing TLR4 in epithelial cells are more susceptible to dextran sodium sulfate (DSS)-colitis and colitis-associated cancer.29
Downregulation or limited activation of PRR signaling intermediates, such as interleukin-1 receptor-associated kinase (IRAK)-1 and NF-κB (Figures 1 and 2 and Tables 1 and 2), further attenuates PRR-initiated responses. IRAK-1 participates in MyD88-dependent9, 30 and some MyD88-independent pathways.30, 31 IRAK-1 degradation following PRR stimulation limits subsequent inflammation in human monocytic cells.20, 31 Furthermore, in non-monocytic cells, such as mouse enterocytes, failure to downregulate IRAK-1 upon postnatal PRR ligand exposure may contribute to necrotizing enterocolitis.32 Consistent with IRAK-1 signaling downregulation preventing excessive inflammation, mice deficient in IRAK-4, a kinase that activates IRAK-1, are protected against endotoxin shock but are more susceptible to bacterial infections.33 IRAK-1 polymorphisms resulting in increased expression and/or kinase activity are associated with more severe sepsis.34, 35 By contrast, human IRAK-4 loss-of-expression mutations increase invasive pneumococcal disease risk.36 Downstream NF-κB signaling is critical for PRR-induced responses and its modulation changes PRR-initiated outcomes. For example, decreased phosphorylation and nuclear translocation of NF-κB subunits downregulates TLR4-mediated signaling in human intestinal macrophages.26 Although NF-κB activation is generally associated with inflammation, its outcomes are more complex; for example, NF-κB directly contributes to anti-microbial responses. Moreover, NF-κB has various regulatory roles, which vary in different intestinal cell subsets, and different NF-κB subunits have distinct functional roles. For example, while p50/p65 NF-κB heterodimers generally induce inflammatory pathways and these individual subunits are essential for proper anti-microbial responses,37, 38 p50/p50 homodimers inhibit inflammatory responses,39, 40 and contribute to endotoxin tolerance in mouse macrophages.41, 42 Similarly, mice deficient in IKKβ (Ikappa B kinase beta) in myeloid cells are more susceptible to endotoxin shock.43 Moreover, mice deficient in p50 and heterozygous for p65 develop spontaneous typhlocolitis.44 However, p65 knock down attenuates experimental colitis,45 and increased PRR-induced NF-κB activation in epithelial cells exacerbates colitis but only if accompanied with MAPK activation and tumor necrosis factor (TNF)-α production.46 Another complexity is that p50 is processed from the NFKB1 gene product p105,39 which exhibits additional regulatory functions, as p105-deficient mice expressing p50 still show increased lung and liver inflammation.47 Importantly, NFKB1 polymorphisms are associated with UC10 and necrotizing enterocolitis,48 and polymorphisms in the NF-κB subunits REL and RELA are associated with IBD;10 the functional consequences of these polymorphisms are unclear. In IBD patients, increased p65 expression and NF-κB-binding activity is seen in intestinal macrophages and epithelial cells.49, 50 Therefore, regulating the expression and function of PRR-signaling pathway intermediates in macrophages occurs on multiple levels. As both loss- and gain-of-function of these molecules can lead to inflammation, fine tuning their regulation is crucial for proper immune homeostasis.
Inhibitory molecules operate by numerous mechanisms to limit pattern-recognition receptor (PRR)-induced macrophage functions. Intracellular inhibitors regulate inflammatory responses on multiple levels by interfering with PRR-initiated signaling. Selected mechanisms of action of intracellular inhibitors are also summarized in Table 2. Inflammatory intermediates are indicated in green and inhibitory molecules in red. ABIN, A20 binding inhibitor of NF-κB; ERK, extracellular signal–regulated kinase; GAS, growth-arrest specific; IFNR, interferon receptor; IRF, interferon regulatory factor; ITAM, immunoreceptor tyrosine activation motif; JAK, Janus tyrosine kinase; MKP, mitogen-activated protein kinase phosphatase; MyD88, myeloid differentiation primary response gene 88; NF-κB, nuclear factor κB; NLR, nucleotide oligomerization domain-like receptor; PI3K, phosphatidylinositol 3-kinase; SHIP, SH2-containing inositol 5′-phosphatase; SOCS, suppressor of cytokine signaling; TLR, Toll-like receptor; TRAF, TNF receptor–associated factor.
Inhibitory molecules regulate PRR signaling by various mechanisms
PRR-induced inflammation can be downregulated through inhibitors targeting PRR-initiated pathways (Figure 2 and Table 2). Some inhibitors are constitutively expressed and inhibit basal cytokine expression and/or initial PRR signaling modulation, whereas others are upregulated after PRR stimulation. Furthermore, inflammation can be regulated by several inhibitory waves following PRR stimulation.51 Inhibitors are often increased in inflamed tissues, as the immune system attempts to control the inflammation. Below, we will discuss examples of inhibition of PRR-initiated responses by surface receptor and intracellular inhibitory molecules. A summary of these and other inhibitors is shown in Figure 2, Tables 1 and 2.
Inhibitory surface receptors or secreted decoy receptors regulate PRR-induced inflammation. For example, initial studies found that ST2 sequesters MyD88 and Mal to prevent TLR4-dependent NF-κB signaling, cytokine induction, and endotoxin tolerance in vivo in mice,52, 53 as well as in human monocytes.54 Subsequently, membrane-bound ST2 (ST2L) was identified as a receptor for IL-33,55 and controversy ensued as to the composite effects of IL-33/ST2L interactions in inhibiting or activating cytokine-inducing pathways. These interactions may differentially affect inflammation in distinct cell types and tissues, including in the intestine.56, 57 In mice, IL-33 binds to ST2 on Th2 (T helper type 2) cells,57 and this interaction promotes Th2-mediated colitis.56 ST2 also exists as a soluble isoform, which is a decoy receptor that binds to IL-33 and inhibits its signaling,58 adding further complexity to the ST2-mediated regulation of inflammatory responses. Polymorphisms in a region containing ST2 (IL1RL1) are associated with Crohn’s disease (CD).59 In UC patients, inflamed mucosa and sera express increased soluble ST2, whereas ST2L expression on the surface of epithelial cells is downregulated, adding further complexity to elucidating the ultimate role of ST2 in IBD.56
IRAK-1 inhibition regulates not only PRR-, but also IL-1R- and IL-18R-induced pathways.9 Basal expression of the IRAK-1-activation inhibitor, IRAK-M, in mouse and human macrophages controls initial PRR-mediated inflammation.31, 60, 61 Chronic infection or PRR stimulation further upregulates IRAK-M in macrophages,31, 60, 62, 63 which, in turn, downregulates cytokine induction following PRR restimulation.31, 60, 62 This partially occurs by preventing IRAK-1 and IRAK-4 dissociation from MyD88, thereby abrogating further IRAK-1-dependent signaling.60 IRAK-M deficiency increases severity of endotoxin shock60 and of mucosal injury models in mice, including in the lung64 and colon.65 Loss-of-function polymorphisms have been associated with inflammatory/autoimmune diseases such as asthma,66 and dysregulated IRAK-M levels are seen in various diseases, including asthma,67 necrotizing enterocolitis,68 tuberculosis,69 and cystic fibrosis.62
TLR3 and TLR4 activate the MyD88-independent TRIF pathway, which induces Type I interferons (IFNs) and IFN-γ. Autocrine interferon-mediated inflammation is, in turn, regulated by the suppressor of cytokine signaling (SOCS) proteins, in particular SOCS-1, which primarily inhibits interferon-initiated JAK/STAT (Janus tyrosine kinase/signal transducer and activator of transcription factor) pathways.70, 71, 72, 73, 74 SOCS-1-deficient mice show early death due to multi-organ inflammation,73 and decreased survival to sublethal TLR4 stimulation.72 Initial papers described SOCS-1 as downregulating TLR4-induced NF-κB;72, 75 however, subsequent studies found the SOCS-1-deficient mouse phenotype was mostly attributable to excessive type I IFN inflammatory effects, rather than defects in direct TLR4 signaling inhibition by SOCS-1.76, 77 Mutations decreasing SOCS-1 expression are associated with immune dysregulation, including increased serum Immunoglobulin E78 and asthma.79 SOCS-1 upregulation can be mediated by the three TAM receptors expressed primarily in myeloid cells: Tyro3, Axl, and Mer.80, 81 Axl also upregulates the transcriptional repressor Twist1 in human macrophages.82 Mer-deficient mice are more susceptible to endotoxin shock.83 Deficiency in all the three TAM receptors and the subsequent lack of SOCS-1 induction results in uncontrolled macrophage-mediated pro-inflammatory cytokine secretion and autoimmunity.81 Besides inhibiting PRR-mediated inflammation,80 TAM receptors regulate DC chemotaxis84 and apoptotic cell phagocytosis and clearance by macrophages.85, 86, 87 Defects in TAM receptor-induced phagocytosis contribute to autoimmunity in TAM-deficient mice.85 Consistently, apoptotic cell ingestion is associated with anti-inflammatory cytokine production and tolerance.88 Increased levels of Protein S, a TAM receptor ligand, are seen in inflammatory diseases such as SLE (systemic lupus erythematosus) and UC;89, 90 the role of this elevation in the disease process is unclear.
An important inhibitor targeting multiple pathways, A20, was initially implicated in terminating TNF-induced NF-κB activation in mice91 through ubiquitinating a TNF signaling intermediate receptor-interacting protein (RIP) and targeting it for degradation.92 Subsequent studies demonstrated that A20 also inhibits PRR-initiated pathways such as the TLR4 pathway through ubiquitinating TRAF6 (TNF receptor–associated factor 6),93 the TLR3 pathway by preventing IRF3 (interferon regulatory factor 3) dimerization,94 and the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) pathway by ubiquitinating and degrading the NOD2 downstream effector RIP2.95 A20-deficient mice die prematurely due to severe multi-organ inflammation.91 Moreover, selective A20 deficiency in DCs induces spontaneous colitis.96 Polymorphisms in the A20 region, including loss-of function mutations, are associated with multiple autoimmune/inflammatory diseases, including CD,97 SLE,98, 99 and rheumatoid arthritis (RA).100, 101 IRF4 inhibits PRR pathways in mouse and human monocytic cells by preventing RIP2102 and MyD88 signaling,103 and decreasing JNK and NF-κB activation.104 Consistently, IRF4−/− mice demonstrate more severe endotoxin shock.103 Furthermore, IRF4 upregulation upon chronic NOD2 stimulation contributes to protection from experimentally induced colitis,102 and IRF4 expression is increased in the mucosa of IBD patients.105
SH2-containing inositol 5'-phosphatase (SHIP-1) inhibits MyD88-independent pathways by dephosphorylating and inhibiting tank binding kinase 1 (TBK1), thereby modulating IFNβ induction.106 SHIP-1 also limits phosphatidylinositol 3-kinase (PI3K) signaling.107 SHIP-1-deficient mice are hyper-responsive to lipopolysaccharide (LPS) stimulation and defective in endotoxin tolerance.107 However, over time SHIP-1 deficiency promotes anti-inflammatory M2 macrophage polarization, possibly to counteract the inflammatory phenotype.108 SHIP-1−/− mice exhibit ileitis109 and increased macrophage infiltration into bone marrow and spleen, which ultimately decreases survival.110 Increased SHIP-1 expression is observed in the intestinal mucosa of IBD patients;111 it is unclear if this increase reflects a compensatory mechanism to counteract the inflammation.
FCγ receptors and β2-integrins containing ITAM domains downregulate multiple PRR pathways by inducing PRR signaling inhibitors, including SOCS-1, A20, and IL-10 in primary human macrophages.112 Consistently, ITAM receptor induction protects from inflammation, including experimental colitis.113, 114 Which specific ITAM-containing receptors mediate inhibitory effects and whether ITAM domain-containing peptides can be used therapeutically in inflammatory diseases has yet to be defined.
Secreted inhibitory mediators downregulate PRR-induced pro-inflammatory pathways in an autocrine and/or paracrine fashion
PRR stimulation results in secretion of autocrine/paracrine factors that can feed back to inhibit PRR pathways directly or indirectly, thereby suppressing inflammatory outcomes. For example, PRR-induced transforming growth factor (TGF)-β can inhibit pro-inflammatory cytokines by degrading their transcripts and suppressing their translation.115 TGF-β also inhibits NF-κB signaling,26 downregulates CD40116 and induces SHIP-1.107 IL-10 also regulates inflammation through multiple mechanisms. IL-10 decreases transcript and protein expression of numerous genes, including pro-inflammatory cytokines,115, 117, 118, 119 and leads to degradation of the MyD88-dependent signaling intermediates IRAK-1 and IRAK-4.120 IL-10 also upregulates inhibitors such as soluble TNFR, IL-1Ra and SOCS-3121 and upregulates STAT3 and PI3K pathways,122 which can inhibit inflammatory pathways.123, 124, 125, 126, 127, 128, 129, 130 Moreover, IL-10 inhibits additional myeloid cell functions, including phagocytosis and antigen presentation.123 Autocrine IL-10 and TGF-β signaling frequently combine to effectively suppress inflammation, including in human macrophages and at mucosal sites.18, 126, 131 Mouse studies have long confirmed the importance of these secretory mediators in homeostasis at mucosal surfaces: IL-10 and TGF-β-deficient mice develop spontaneous colitis.132 Depleting macrophages in IL-10-deficient mice attenuates the colitis,133 demonstrating that dysregulated macrophage function contributes to disease. Besides downregulating inflammation in macrophages proper, IL-10 production by gut macrophages suppresses inflammation by modulating other cell subsets, such as intestinal FoxP3+ T cells.134 Mice with deletion or loss-of-function of the TGF-β receptor in myeloid cells show impaired DSS-colitis resolution,135 indicating that besides producing TGF-β myeloid cells must also respond to TGF-β to limit intestinal inflammation. Consistently, TGF-β is required for downregulating pro-inflammatory cytokines in human lamina propria macrophages.136 Importantly, human polymorphisms in regions including IL10, IL10R, and SMAD3 are associated with autoimmune/inflammatory diseases, including IBD.10, 137, 138 An additional PRR-induced secretory mediator, IL-1Ra, inhibits IL-1R signaling.139 As autocrine/paracrine IL-1 dramatically enhances overall cytokine secretion by human macrophages, IL-1Ra ultimately downregulates multiple cytokines (Figure 1).140 Consistently, IL-1Ra deficiency or blockade worsens experimental colitis141 and increases endotoxin susceptibility in mice,142 and loss-of-function IL-1Ra polymorphisms are associated with autoimmune diseases143 (Table 1).
Emerging evidence shows that in specific circumstances, cytokines with pro-inflammatory roles such as IL-1β,126 interferons,82, 144 and TNF-α,61, 145, 146 can, in fact, also downregulate PRR- and FCγR-mediated inflammation in human macrophages. Mechanisms mediating these anti-inflammatory responses can include induction of certain inhibitory proteins and inhibitory signaling pathways (e.g., GSK3 (glycogen synthase kinase-3) signaling).61
Distinct isoforms and strength of signaling modulate PRR-induced macrophage outcomes
Targeting of MAPK and PI3K signaling pathways is being studied in therapeutic trials.147, 148 As modulating the quality and/or quantity of these pathways determines whether they activate or inhibit PRR-initiated pathways (Figure 1), an improved understanding of their signaling would more accurately predict therapeutic outcomes.
Extracellular signal–regulated kinase (ERK) can inhibit LPS-induced pro-inflammatory cytokines in mouse macrophages.149, 150 However, this inhibition has not generally been observed in human studies.151, 152 More recent studies in human macrophages identified that PRR-induced ERK indeed inhibits pro-inflammatory cytokines but that this inhibition is masked by autocrine IL-1, which then increases the strength of MAPK signaling and modifies the downstream outcomes.153 Differential susceptibility to lowering ERK signaling can be observed between different pro-inflammatory cytokines as well, such that IL-1β secretion decreases upon ERK inhibition more readily than TNF-α in LPS-stimulated mouse macrophages.154 Therefore, the strength of MAPK signaling can dramatically influence whether pro-inflammatory cytokine secretion is inhibited or enhanced in macrophages.
PI3K can both downregulate124, 125, 126, 127, 128, 129, 130 and upregulate155, 156 pro-inflammatory signaling. PI3K consists of multiple subunits,157 which could contribute to these observed differences,124, 130, 158, 159 as could differential strength of PI3K signaling induced by distinct PRR. Furthermore, the subunits targeted vary between different pharmacological PI3K inhibitors and the inhibitor concentrations used. In human disease, targeting the PI3K substrate mTOR (mammalian target of rapamycin) induces tolerance during transplantation by upregulating regulatory T cells.148 However, rapamycin inhibits PRR-mediated tolerance in human macrophages,126 and mTORC1 deficiency in DCs exacerbates DSS-induced colitis.160 Therefore, although PI3K and mTOR signaling can negatively regulate PRR-initiated inflammatory pathways in macrophages, this signaling in T cells can lead to distinct outcomes.
microRNAs inhibit PRR signaling on a transcriptional level
A rapidly developing field of PRR-signaling regulation is microRNAs (Figure 1). MicroRNAs regulate inflammation through targeting the 3' untranslated region of transcripts leading to either their stabilization or degradation.161 Such regulation is central to fine-tuning inflammatory responses. Interestingly, microRNAs can modify expression levels of both the positive and negative PRR-signaling regulators, including MyD88 signaling intermediates, transcription factors, cytokines, and inhibitors. Multiple microRNAs have been associated with TLR signaling,161 with miR-146 and miR-155 being prominent in regulating inflammation.161 For example, miR-146 inhibits IRAK-1 expression in human macrophages, thereby decreasing NF-κB activation and pro-inflammatory cytokine induction.162 Polymorphisms altering miR-146 expression are associated with SLE and RA.163 Similarly, miR-23b, which suppresses multiple pro-inflammatory molecules, ameliorates mouse lupus, RA, and MS models and is downregulated in human autoimmune diseases, including RA.164 By contrast, microRNAs such as miR-155 that downregulate PRR-signaling inhibitors are increased in macrophages from RA patients. Consistently, miR-155-deficient mice are protected against experimental arthritis.165 Interestingly, microRNAs can act as TLR7 and TLR9 agonists, inducing paracrine inflammatory responses.166 Multiple human inflammatory diseases, including UC167 and RA,168 show dysregulated microRNA profiles. Expression and function of microRNAs can vary in human and mouse immune cells;169 elucidating these differences is crucial to understanding the mechanisms through which distinct microRNAs regulate separate human macrophage functions.
Epigenetic regulation of PRR signaling
Immune cell phenotypes can be broadly modulated by epigenetic modifications (Figure 1). Upon PRR restimulation of mouse and human macrophages following chronic LPS stimulation, some genes are repressed (“tolerant”), whereas others remain transcribed (“non-tolerant”);16, 17 such outcomes are partially regulated through epigenetic modifications. The tolerant genes largely include inflammatory genes, while the non-tolerant genes mediate microbial killing and inhibit inflammation.16 Importantly, in mucosal tissues such as the intestine, which chronically encounter microbial products, the epigenetic regulation mediating this dual transcriptional and functional regulation may ultimately enhance anti-microbial function while minimizing tissue inflammation and injury. In mouse lamina propria myeloid cells, bacterial-induced IL-10 was found to downregulate IL-12p40 through histone deacetylase 3 (HDAC3)-mediated histone deacetylation.170 However, overall epigenetic regulation of intestinal macrophages is poorly defined. In primary human DCs and THP-1 macrophages, acute LPS stimulation results in histone acetylation and H3K4 methylation (both activating transcription) in pro-inflammatory cytokine and activation marker genes.171, 172 However, during endotoxin tolerance, inhibitory histone methylation (e.g., H3K27) is observed on pro-inflammatory genes in these cells.172, 173, 174 Interestingly, a polymorphism in TLE1, a HDAC-interacting transcription factor, is associated with CD.175 On the other hand, HDAC inhibitors improve experimental colitis and kidney disease in mice176, 177 and are undergoing evaluation as therapy for inflammatory diseases, such as systemic onset juvenile idiopathic arthritis178 and IBD.179 The therapeutic properties of HDAC inhibitors are incompletely understood and may involve mechanisms independent of inflammatory gene regulation, including protein acetylation and the induction of apoptosis.180
Inflammasomes regulate PRR-induced inflammation and are associated with human inflammatory diseases
Microbial stimuli can activate inflammasomes, macromolecular complexes containing NLR family members activating caspase-1, which cleaves pro-IL-1β and -IL-18 into their active forms (Figure 1).181 Multiple NLRs contribute to inflammasome diversity,181 although not all NLR proteins form inflammasomes. Tight balance of inflammasome regulation is crucial; inhibition or deletion of inflammasome components can either ameliorate or exacerbate animal inflammatory disease models. For example, ASC-deficient mice are more resistant to endotoxin shock,182 and caspase-1 deficiency attenuates DSS colitis.183 However, NLRC4 and NLRP6 deficiency exacerbates experimental mouse colitis, partially through dysregulated inflammatory cytokines, including IL-18, and altered intestinal microbiota.184, 185 Furthermore, polymorphisms in NLRs and molecules regulating inflammasome activation are associated with the autoinflammatory diseases.186, 187, 188 Inflammasome-associated pathways also mediate mucosal-associated inflammatory diseases as evidenced by the association of NLRP1 to vitiligo and systemic sclerosis,189, 190 NOD2 to CD,191, 192 and CARD9, IL-18RAP/IL12RL2/IL18R1/IL1RL1 and IL1R2 regions to IBD.10, 59 Unlike the activating role of many NLRs, most, but not all,193 reports find that NLRP12 inhibits inflammation.194, 195 Consistently, NLRP12-deficient mice are more susceptible to DSS-induced colitis and colitis-associated tumorigenesis,196 although not to airway hypersensitivity.197 NLRP12 loss-of-function mutations are associated with inflammatory diseases,198, 199 including atopic dermatitis.200 Studies defining diseases that benefit from targeting either the inflammasome directly or the products of inflammasome activation (e.g., IL-1, IL-18) are ongoing.201
Autophagy regulates multiple macrophage functions
PRR stimulation induces autophagy, which facilitates cellular organelle and bacterial clearance.202 In vivo mouse studies and human genetic association studies have demonstrated that autophagy-associated genes and pathways are essential for intestinal homeostasis;203, 204, 205, 206, 207 loss-of-function polymorphisms in the autophagy genes ATG16L1 and IRGM are associated with CD.10, 208 These polymorphisms impair bacterial killing in some,203, 207, 209 but not all, situations.207, 210 ATG16L1 hypomorphic mice have dysregulated Paneth cell morphology and exhibit microbiota-driven intestinal inflammation.205, 211 Moreover, ATG16L1 can contribute to anti-viral activity in macrophages in an autophagy-independent manner.212 Interestingly, besides mediating bacterial killing, autophagy downregulates cytokine production from myeloid cells. Recent mouse studies demonstrate that autophagy promotes absent in melanoma 2 (AIM2) and NLRP3 inflammasome degradation213 and decreases IL-1 secretion.214, 215 Human peripheral blood mononuclear cells studies show that autophagy also downregulates IL-1 through degrading IL-l transcripts.216 Therefore, autophagy regulates at least two distinct and critical PRR-mediated functions: (1) microbial clearance and (2) cytokine downregulation (Figure 1). These dual functions are crucial in the intestine, thereby highlighting fundamental mechanisms through which autophagy can contribute to intestinal immune homeostasis.
PRR Signaling in Intestinal Macrophages is Mediated by Diverse Local Factors
In previous sections, we discussed mechanisms inhibiting PRR-mediated functions and emphasized in select places how some of these mechanisms contribute to intestinal macrophage function and intestinal homeostasis; here we focus specifically on aspects of the unique phenotype observed in intestinal macrophages and on additional factors and mechanisms contributing to this phenotype. Intestinal macrophages constitute one of the largest reservoirs of myeloid cells.25, 217 Macrophages are located throughout the intestinal tract,25, 218 but most prominently in the lamina propria, beneath the protective epithelial layer, making macrophages particularly important in bacterial recognition following bacterial translocation during events such as epithelial injury.25 Relative to peripheral monocyte-derived cells, intestinal macrophages secrete low levels of pro-inflammatory cytokines upon PRR stimulation but upregulate bacterial killing.136, 219, 220 This limits unnecessary inflammation and tissue damage while simultaneously protecting against overgrowth of resident microbiota and pathogenic bacteria. As peripheral monocytes enter the intestinal lamina propria, multiple local mechanisms contribute to their differentiation into intestinal macrophages.25 Contributing factors include microbial components (e.g., PRR ligands, polysaccharide A221), anti-inflammatory mediators (e.g., TGF-β, IL-10), nutrients, and apoptotic cells. Notably, during acute infection or tissue injury, intestinal macrophages can mount inflammatory responses.220 This inflammation can be mediated by peripheral monocyte recruitment to the intestine; the intestinal microenvironment can then influence subsequent differentiation patterns.222, 223, 224, 225, 226, 227 Consistently, altered proportions, functions, and/or differentiation of intestinal myeloid cells can lead to intestinal inflammation in mice,222, 228, 229, 230, 231, 232, 233, 234, 235, 236 and myeloid cell dysregulation in human intestine is observed in IBD.237, 238
Consistent with decreased pro-inflammatory cytokine secretion, intestinal macrophages demonstrate downregulated CD14, MD2, TLR2, TLR4, MyD88, and IRAK-1, and decreased NF-κB activation, although certain PRR (e.g., TLR3, 5–9) are expressed.26, 136 Chronic PRR stimulation could contribute to downregulated inflammation in intestinal macrophages. For example, chronic NOD2 stimulation downregulates cytokines in myeloid-derived cells31, 102, 126 and protects mice from experimental colitis.102 Interestingly, intestinal myeloid cells from germ-free mice show downregulated PRR-mediated cytokine secretion,170, 220 although these mice were exposed to PRR ligands through food and bedding. To clearly dissect the role of chronic PRR stimulation in the downregulated cytokines observed in intestinal macrophages, germ-free mice will need to be examined under conditions of food and bedding devoid of microbial products, combined with recurrent intestinal injury. Stromal and epithelial cell secretions (e.g., TGF-β, IL-10, retinoic acid, and thymic stromal lymphopoietin) can also downregulate intestinal myeloid cell responses.26, 136, 239, 240, 241, 242 For example, TGF-β signaling in DCs regulates intestinal inflammation in mice,243 and intestinal stromal cell-derived TGF-β downregulates CD14 expression, NF-κB activation, and PRR-induced cytokine secretion in peripheral human monocytes.26, 136, 240 Nutrients, including vitamin D and retinoic acid that are abundant in the intestine, also contribute to intestinal macrophage tolerance. Vitamin D downregulates PRR-induced pro-inflammatory cytokines from human monocytes.244 Consistently, vitamin D administration attenuates experimental mouse colitis.245, 246 Furthermore, higher vitamin D plasma levels correlate to decreased CD risk.247 Conversely, compared with healthy controls, CD patients exhibit vitamin D deficiency,248 which is multi-factorial in etiology, and correlates to disease severity.249 Similarly, in addition to its immunoregulatory roles in T cells,250 retinoic acid downregulates pro-inflammatory cytokines in PRR-stimulated human DC.251 Finally, intestinal macrophages ingest apoptotic cells, which leads to TGF-β and prostaglandin production.252, 253, 254 Importantly, mice lacking intermediates in apoptosis-inducing pathways, such as TAM receptors, C1q, MFG-E8, and TIM-4, develop autoimmunity.86, 255, 256, 257 Moreover, autophagy clears apoptotic debris,258 highlighting one mechanism through which autophagy dysfunction may contribute to IBD susceptibility.203, 204, 205, 206, 207
Despite downregulated cytokines, human intestinal macrophages upregulate bactericidal activity. Intestinal factors can mediate both processes. PRR16, 17 and Vitamin D259, 260 stimulation of human and mouse macrophages upregulates multiple anti-microbial pathways. Interestingly, some studies show bactericidal defects in CD patient macrophages.261 As heterogeneous mechanisms lead to CD, bactericidal defects likely exist in a subset of CD patients, such as those carrying polymorphisms in bactericidal pathways (e.g., NOD2, ATG16L1, IRGM, and NCF-2).10, 262 Targeting mechanisms mediating the dichotomy of downregulated inflammatory and upregulated bactericidal pathways in human intestinal macrophages might be particularly beneficial in IBD therapy.
Human and Mouse Macrophages Demonstrate Distinct Regulation in Various Pathways
Human and murine-based studies are essential and complementary to defining mechanisms of disease pathogenesis. There are multiple, fundamental differences between human and mouse PRR signaling outcomes,11, 12 including distinct PRR and cytokine stimulation responsivity,31, 102, 263, 264, 265, 266, 267 and differential PRR utilization.268 These differences are critical when extending mouse findings to human physiology and disease. Reasons for inter-species differences include distinct function and/or expression of relevant genes, dissimilar life spans, distinct microbial colonization, and altered environmental exposures. Furthermore, human genetic diversity is greater than that of experimental inbred mice, adding significant complexity, but also unique opportunities, in pursuing human immunology.
Different factors regulate mouse and human macrophage polarization
As macrophages enter or are activated in various microenvironments, they differentiate into distinct subtypes, characterized by differential surface marker, cytokine, and protein expression. Two broad categories of polarized mouse macrophages include classically activated macrophages (M1), associated with pro-inflammatory cytokine secretion, and alternatively activated macrophages (M2), associated with an anti-inflammatory phenotype.6 Distinct factors mediate mouse and human macrophage polarization and macrophage phenotypes. M1- and M2-like human macrophages exist269, 270 but are less well defined than their mouse counterparts. IFN-γ stimulation of mouse, but not human M1 macrophages, dramatically induces NOS2, and IL-4-stimulated human macrophages produce significantly less arginase than mouse M2 macrophages.270 Human macrophage polarization likely involves specific transcription factors. Although in one study, IRF5 mediated M1, and IRF4 mediated M2 polarization of human macrophages,269 another study found contrasting results.271 Notably, IRF5 is central to macrophage function as evidenced by IRF5 polymorphism associations with numerous autoimmune/inflammatory diseases exhibiting dysregulated cytokine expression272 and the dramatic contribution of IRF5 polymorphisms to human variance in PRR-induced cytokine secretion.273 Another IRF family member, IRF8, has been recently shown to promote mouse M1 polarization;274 IRF8 effects on human macrophage polarization are still unclear. Further studies are needed to better define the regulation of human macrophage polarization and how this polarization contributes to immune homeostasis.
Mouse and human macrophages demonstrate differences in inflammasome activation
PRR stimulation induces pro-IL-1β, but a second signal, such as adenosine triphosphate (ATP), is required to activate P2 × 7 receptors. This results in potassium efflux and calcium influx, which activates the inflammasome and induces caspase-1-mediated processing of pro-IL-1β and -IL-18 to their active forms.275, 276, 277 Tissue damage releases ATP,278 thereby providing a second signal to mouse macrophages.279 However, PRR-ligand stimulated human monocytes secrete autocrine ATP;280 therefore, PRR-stimulation alone induces IL-1β in these cells. Some studies demonstrate that PRR-stimulated human macrophages do not secrete IL-1β,281, 282 with a second stimulus necessary for IL-1β secretion.283 However, others detect active IL-1β in PRR-stimulated human macrophages due to the sufficiency of PRR stimulation for ATP production.140, 153, 284, 285, 286 These differences might partially reflect different culture conditions used to generate macrophages; growth factor and cytokine differences can profoundly influence human macrophage responses.287 Improved insight into differential regulation of IL-1 in human and mouse macrophages will be important, as IL-1 contributes to multiple human diseases,201 and autocrine/paracrine IL-1β dramatically amplifies PRR-induced cytokine secretion in human macrophages.140, 153
Human variance adds complexity to examination of PRR-induced macrophage functions
Mouse studies minimize variance in PRR-induced inflammatory outcomes through inbreeding, housing in conditions that reduce environmental differences, and utilizing age-, gender-, and littermate-matched mice. However, humans show significant variance in their genetic background,288 environmental exposures,289, 290 and intestinal microbiota,291, 292, 293, 294 which translates into broad inter-individual immunological differences. For example, there is dramatic inter-individual variation in cytokine and inhibitor molecule induction upon PRR stimulation in human macrophages.31, 61, 273, 295, 296, 297, 298 Such variance likely affects the balance between susceptibility to infections versus autoimmune/inflammatory diseases. Genes identified to regulate variance in human cytokine secretion include IRF5, IL-1Ra, and TLR1. IRF5 polymorphisms account for up to 53% of variance in PRR-induced TNF-α secretion from human monocyte-derived cells;273 this dramatic contribution likely results from the distinct genotypes being commonly distributed across the population and from the dramatic gene-dose-dependent regulation mediated by IRF5 polymorphisms. IL-1Ra polymorphisms mediate 5% of variance in constitutive IL-1β plasma levels,299 and TLR1 polymorphisms contribute to variance in IL-6 secretion during sepsis.297 Perhaps not coincidentally, these polymorphisms contribute to susceptibility and/or outcomes in multiple inflammatory/autoimmune diseases associated with dysregulated cytokine production.272, 297, 299 Importantly, inhibitory mechanisms regulating PRR-initiated pathways demonstrate varying contributions in myeloid cells from different individuals (e.g., IRAK-M and SHIP-1).31, 61 Of note is that mutations modulating inflammatory pathway intermediates, such as MyD88300 and TRIF,301 may dramatically affect cytokine induction, but if relatively rare, will not significantly influence overall inter-individual heterogeneity. Another consideration is that some PRR-pathway polymorphisms (e.g., NOD2,302, 303 TLR4304), have different frequencies across distinct ancestries, which will therefore influence the inter-individual differences upon PRR stimulation between population groups. Host–microbe interactions are central in natural selection and functional variation; the inter-individual variability inherent in human immunological studies can ultimately be leveraged to define underlying mechanisms of autoimmune-mediated diseases.305
Another contribution to variance in human immune responses is inter-individual differences in microbial composition. Multiple mouse studies have implicated intestinal microbiota in regulating immunity and disease development, including mucosal diseases.185, 221, 306, 307, 308 Altered human intestinal microbial composition is also associated with dysregulated immunity and disease;291, 292, 293, 294 it is unclear to what degree these microbial changes are a consequence or a cause of the inter-individual immunological differences.
Taken together, mouse models have provided tremendous insight into defining the importance of various pathways and functions in myeloid-derived cells in health and in disease development. Furthermore, humanized mice can be used to address select in vivo myeloid cell functions given successful reconstitution of human myeloid cells into mice.309 However, in applying the information from mouse studies to human immune function, it is critical to understand the similarities and differences between mouse and human immune pathways.
Future Perspectives
Despite significant advances in understanding human macrophage regulation and functions, multiple questions remain. What are the functional outcomes of the many disease-associated polymorphisms in macrophages? Which factors influence human macrophage polarization? How do monocytes acquire distinct resident phenotypes as they enter tissues? How do intestinal macrophages determine when to maintain tolerance and when to mount inflammatory responses to resident or pathogenic bacteria?
Human heterogeneity poses a specific challenge when conducting human macrophage studies; sampling from well-powered cohorts is essential. Moreover, limited tissue access restricts the number of functional immunological readouts; high throughput approaches minimizing sample sizes are continuously being developed and improved. Uniform sample processing, standard operating techniques and normalization of immune readouts based on criteria, including age, gender, ancestry, or specific genotypes, will be essential for future studies. Despite these challenges, elucidating the inhibitory mechanisms in primary human macrophages is essential to fully understand mechanisms mediating both health and disease.
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Acknowledgements
We gratefully acknowledge Judy Cho for critical reading of the manuscript. This work was supported by R01DK077905, DK-P30-34989, and U19-AI082713 (CA).
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Hedl, M., Abraham, C. Negative regulation of human mononuclear phagocyte function. Mucosal Immunol 6, 205–223 (2013). https://doi.org/10.1038/mi.2012.139
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DOI: https://doi.org/10.1038/mi.2012.139
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