Alveolar macrophages: plasticity in a tissue-specific context

Journal name:
Nature Reviews Immunology
Volume:
14,
Pages:
81–93
Year published:
DOI:
doi:10.1038/nri3600
Published online

Abstract

Alveolar macrophages exist in a unique microenvironment and, despite historical evidence showing that they are in close contact with the respiratory epithelium, have until recently been investigated in isolation. The microenvironment of the airway lumen has a considerable influence on many aspects of alveolar macrophage phenotype, function and turnover. As the lungs adapt to environmental challenges, so too do alveolar macrophages adapt to accommodate the ever-changing needs of the tissue. In this Review, we discuss the unique characteristics of alveolar macrophages, the mechanisms that drive their adaptation and the direct and indirect influences of epithelial cells on them. We also highlight how airway luminal macrophages function as sentinels of a healthy state and how they do not respond in a pro-inflammatory manner to antigens that do not disrupt lung structure. The unique tissue location and function of alveolar macrophages distinguish them from other macrophage populations and suggest that it is important to classify macrophages according to the site that they occupy.

At a glance

Figures

  1. Leukocyte interactions in the healthy lungs.
    Figure 1: Leukocyte interactions in the healthy lungs.

    Alveolar macrophages reside in the airspaces juxtaposed with type I alveolar epithelial cells (which account for as much as 98% of the total surface area of the lungs157) or with type II alveolar epithelial cells . Macrophages found in the larger airways (also referred to in this Review as alveolar macrophages) reside within the mucous layer. Mucus-producing goblet cells are present in both large and small airways, and secretory non-ciliated Clara cells are more common in the bronchioles158. Macrophages are also found in the interstitial space between the alveoli and the blood vessels where T cells, dendritic cells (DCs) and a sparse population of B cells also reside. Commensal (and pathogenic) bacteria reside within the airway mucosa and in the alveoli. a | Alveolar macrophages are regulated by the airway epithelium through their interactions with CD200, which is expressed by type II alveolar cells, with transforming growth factor-β (TGFβ), which is tethered to the epithelial cell surface by αvβ6 integrin, and with secreted interleukin-10 (IL-10). These interactions can also take place in the larger airways, where CD200 and αvβ6 integrin are also expressed by the bronchial epithelium. b | The secretion of TGFβ and retinoic acid by alveolar macrophages can induce forkhead box P3 (FOXP3) expression in both naive and activated CD4+ T cells that are present in the lumen of the airways. In addition, TGFβ and prostaglandins suppress T cell activation. CD200R, CD200 receptor; IL-10R, IL-10 receptor; TGFβR, TGFβ receptor.

  2. Negative regulators of alveolar macrophage activation.
    Figure 2: Negative regulators of alveolar macrophage activation.

    Alveolar macrophages are restricted by soluble mediators in the lumen of the airways and by cell–cell interactions, for example, with bronchial and alveolar epithelial cells. Interleukin-10 (IL-10) is abundant in the lungs and restricts inflammation by triggering the Janus kinase 1 (JAK1)–signal transducer and activator of transcription 3 (STAT3) pathway to induce the expression of negative regulators such as suppressor of cytokine signalling 3 (SOCS3) and the microRNA miR-146b. SOCS3 blocks the expression of pro-inflammatory cytokines, whereas miR-146b directly inhibits Toll-like receptor 4 (TLR4) expression and signalling. Transforming growth factor-β (TGFβ) regulates inflammation through both SMAD-dependent and SMAD-independent signalling pathways. The αvβ6 integrin is mainly expressed on bronchial epithelial cells, but is also expressed on inflamed alveolar epithelial cells. Binding of latent TGFβ by αvβ6 integrin induces a conformational change in TGFβ that facilitates access of the TGFβ receptor (TGFβR) to the αvβ6 integrin-bound TGFβ. Triggering receptor expressed by myeloid cells 2 (TREM2), via the adaptor molecule DNAX-activation protein 12 (DAP12), negatively restricts inflammation in macrophages by binding to a currently unknown ligand or ligands. The mannose receptor blocks the recognition of TLR4 ligands and restricts phagocytosis of pathogens such as Pseudomonas aeruginosa. The CD200 receptor (CD200R) interacts with CD200 on the respiratory epithelium, recruiting docking protein 2 (DOK2) and RAS GTPase-activating protein RASA2 (also known as RASGAP), which blocks the extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and JUN N-terminal kinase (JNK) inflammatory pathways. Pulmonary surfactant-associated protein A (SPA) and SPD are abundant in the airways and block TLR2 and TLR4 interactions with their respective ligands, as well as their interactions with the TLR co-receptors MD2 and CD14, which prevents the activation of nuclear factor-κB (NF-κB) and the initiation of the inflammatory response. Binding of surfactant proteins to signal-regulatory protein-α (SIRPα) recruits SH2 domain-containing protein tyrosine phosphatase 1 (SHP1) and activates RHOA, which inhibits phagocytosis. IL-10R, IL-10 receptor.

  3. The balancing act of macrophage activation.
    Figure 3: The balancing act of macrophage activation.

    Alveolar macrophage activation and the initiation of inflammation involves a complex balancing act between activating and repressing signals. On the one hand, Toll-like receptors (TLRs), along with their co-receptors such as MD2 and CD14, recognize pathogen-associated molecular patterns and receptors for inflammatory cytokines, such as tumour necrosis factor (TNF), interleukin-1β (IL-1β) and interferon-γ, which perpetuate inflammation. On the other hand, mediators such as IL-10 and soluble or αvβ6 integrin-tethered transforming growth factor-β (TGFβ) block pathways that lead to inflammation. Cell–cell interactions with bronchial or alveolar epithelial cells also deliver inhibitory signals to alveolar macrophages, for example, through CD200 receptor (CD200R), triggering receptor expressed by myeloid cells 2 (TREM2) or signal-regulatory protein-α (SIRPα). Loss of the ligands for the negative regulators, for example, following epithelial cell loss during inflammation, will tip the balance towards alveolar macrophage activation. Conversely, increased expression of the negative regulators and inhibition of TLR signalling pathways, for example, in the resolution of inflammation, tips the balance towards the repression of alveolar macrophages. IFNGR, interferon-γ receptor, IL-1R, IL-1 receptor; TGFβR, TGFβ receptor; TNFR, TNF receptor.

  4. Altered macrophage regulation after inflammation.
    Figure 4: Altered macrophage regulation after inflammation.

    Following the resolution of inflammation, alveolar macrophages have an increased regulatory level compared to naive macrophages. CD200 receptor (CD200R) and triggering receptor expressed by myeloid cells 2 (TREM2) expression is markedly increased following influenza or house dust mite-induced allergic airway disease in mice, and there is more soluble interleukin-10 (IL-10) present in the lungs. Conversely, the expression of macrophage receptor with collagenous structure (MARCO), which is a scavenger receptor involved in the clearance of bacteria, is reduced after inflammation. In addition, several months after the resolution of an influenza infection, mouse airway macrophages are restricted in their responsiveness to the Toll-like receptor (TLR) agonists lipopolysaccharide (LPS; in the case of TLR4), lipoteichoic acid (LTA; in the case of TLR2) and flagellin (in the case of TLR5), and they have impaired nuclear factor-κB (NF-κB) translocation to the nucleus after TLR5 activation (dashed arrows). IL-10R, IL-10 receptor.

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Affiliations

  1. Manchester Collaborative Centre for Inflammation Research, University of Manchester, 2nd floor, Core Technology Facility, Oxford Road, Manchester M13 9PT, UK.

    • Tracy Hussell &
    • Thomas J. Bell

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The authors declare no competing interests.

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  • Tracy Hussell

    Tracy Hussell trained in mucosal immunology at University College London, UK, where she gained her Ph.D. She was awarded a Professorship in Inflammatory Disease at Imperial College London, UK, in 2008 and is now the director of the Manchester Collaborative Centre for Inflammation Research (MCCIR), UK. MCCIR homepage.

  • Thomas J. Bell

    Thomas J. Bell trained for his Ph.D. on the Wellcome Trust Molecular and Cellular Basis of Infection programme at Imperial College London, UK, and is now at the Manchester Collaborative Centre for Inflammation Research, UK, where he is investigating macrophage polarization in the repairing lungs.

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