Review Article | Published:

Mechanisms regulating skin immunity and inflammation

Nature Reviews Immunology volume 14, pages 289301 (2014) | Download Citation

Abstract

Immune responses in the skin are important for host defence against pathogenic microorganisms. However, dysregulated immune reactions can cause chronic inflammatory skin diseases. Extensive crosstalk between the different cellular and microbial components of the skin regulates local immune responses to ensure efficient host defence, to maintain and restore homeostasis, and to prevent chronic disease. In this Review, we discuss recent findings that highlight the complex regulatory networks that control skin immunity, and we provide new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation.

Key points

  • Monocytes and macrophages are increasingly recognized as important effector cells in inflammatory skin reactions. Depending on the cytokine milieu, they can either promote or attenuate the inflammatory response. In addition, they function in immune surveillance, thereby supporting the early detection of environmental threats.

  • An increased understanding of different dendritic cell subsets in the skin, their developmental origin and dependence on different transcription factors and their contribution to various effector states of skin immunity opens new avenues for immune modulation.

  • Recent studies have highlighted the importance of tissue-resident memory lymphocytes in establishing both effector and regulatory immune memory at skin tissue sites and the role of these cells in providing protection from pathogens.

  • Epidermal keratinocytes have important immunoregulatory functions and contribute to the maintenance of immune homeostasis and the regulation of immune and inflammatory responses in the skin. Studies in mouse models suggest that keratinocyte-intrinsic mechanisms can contribute to the initiation of skin inflammation.

  • Microorganisms that colonize the surface of the skin interact with epithelial and immune cells and have important functions in regulating immune homeostasis and inflammation in the skin.

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Acknowledgements

The authors apologize to all of the authors whose work could not be discussed and cited owing to space limitations. The authors acknowledge support from the following grant funding bodies: M.P. and I.H. are supported by grant SFB829 from the Deutsche Forschungsgemeinschaft (DFG), Germany; M.P. is supported by the DFG (grants SFB670 and SPP1656), the European Research Council (2012-ADG_20120314), the European Commission (FP7 grants 223404 (Masterswitch) and 223151 (InflaCare)), the Deutsche Krebshilfe Association, Germany (grant 110302), the Else Kröner-Fresenius-Stiftung Foundation, Germany, and the Helmholtz Alliance Preclinical Comprehensive Cancer Center, Germany; I.H. is supported by the Deutsche Krebshilfe Association (grant 109798); F.O.N. is supported by the European Commission (FP7 grant agreement HEALTH-F2-2011-261366) and the Wellcome Trust (programme GR078173MA). The authors' research is funded and supported in part by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, UK. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health.

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Affiliations

  1. Institute for Genetics, Center for Molecular Medicine, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany.

    • Manolis Pasparakis
  2. Department of Dermatology, University of Cologne, Kerpener Strasse 62, D-50931 Cologne, Germany.

    • Ingo Haase
  3. St John's Institute of Dermatology and Guy's and St Thomas' Hospital National Institute for Health Research Biomedical Research Centre, King's College London, SE1 9RT London, UK.

    • Frank O. Nestle

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Manolis Pasparakis or Ingo Haase or Frank O. Nestle.

Glossary

Langerhans cells

A dendritic cell population named after the German anatomist Paul Langerhans. Langerhans cells are derived from monocytes and reside in the epidermis and epithelium of hair follicles, as well as in mucosal body surfaces. They are professional antigen- presenting cells and have immune surveillance functions.

Dendritic epidermal T cells

(DETCs). A population of T cells present in mouse skin. DETCs express CD3 and a T cell receptor, and they derive from the fetal thymus. Following activation, DETCs can secrete large amounts of pro-inflammatory mediators, which participate in the communication between DETCs, neighbouring keratinocytes and Langerhans cells.

Fibrocytes

A population of mesenchymal cells that reside in connective tissues. Fibrocytes have minimal cytoplasm and lack biochemical evidence of protein synthesis. Fibrocytes can migrate from the blood into connective tissues and have roles in wound healing and fibrotic tissue repair.

Activator protein-1

(AP-1). A heterodimeric transcription factor composed of several different subunits of the FOS, JUN, ATF and JUN-dimerization protein families. AP-1 regulates gene expression in response to cytokines, growth factors and infectious agents, and controls basic cellular processes such as proliferation, differentiation and apoptosis.

Motheaten phenotype

A mouse phenotype caused by homozygous mutation of Ptpn6, the gene encoding SH2 domain-containing protein tyrosine phosphatase 1. It is a commonly used model of autoimmune and inflammatory disease. Motheaten mice develop chronic inflammation of the skin, produce autoantibodies and eventually succumb to lethal inflammation of the lungs.

M1 macrophages

A pro-inflammatory or 'classically activated' subset of macrophages that is characterized by phagocytic activity and the expression of particular pro-inflammatory cytokines (such as tumour necrosis factor) and pro-inflammatory mediators (such as inducible nitric oxide synthase).

M2 macrophages

A pro-angiogenic or 'alternatively activated' subset of macrophages that is characterized by the expression of particular angiogenic cytokines (such as vascular endothelial growth factor) and anti-inflammatory mediators (such as arginase and interleukin-10).

Wound-healing macrophages

A subset of macrophages that support tissue repair by enhancing granulation tissue formation and accelerating epithelialization.

Cryopyrin-associated periodic syndromes

A family of autoinflammatory syndromes, including familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal-onset multisystem inflammatory disease. These conditions share many clinical features (such as urticarial skin rash) and are associated with mutations in the gene encoding NLRP3 (NOD-, LRR- and pyrin domain-containing 3; also known as cryopyrin), which is a component of the inflammasome that regulates interleukin-1β production.

Resolvins

Lipid mediators that are induced during the resolution phase following acute inflammation. They are synthesized in a transcellular manner from the essential omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid.

Protectins

A family of compounds that are derived from docosahexaenoic acid and that are characterized by a conjugated triene-containing structure. They have been shown to regulate the influx of neutrophils at inflammatory sites.

Oxazolone-induced dermatitis

A model of dermatitis in which the potent chemical allergen 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one is used experimentally to induce a delayed-type contact hypersensitivity reaction in mice.

Xenotransplant models

The current gold standard for clinically relevant psoriasis models. Inflamed or symptomless skin from patients with psoriasis is transplanted into immunosuppressed mice and the development of lesions is followed over time. Such models have the disadvantage of a low throughput owing to the limited availability of patient-derived skin and they require careful standardization.

Parabiotic mice

Mice in which the blood circulation has been joined surgically. Parabiotic mice share the blood circulation and exchange blood cells, such as lymphocytes, which allows the study of the role of circulating immune cells compared with tissue-resident immune cells.

Wound healing

The sequence of events initiated after tissue injury that lead to its repair. The wound-healing response consists of four phases: coagulation, inflammation, proliferation and remodelling. It leads to the formation of a fibrotic replacement scar tissue.

Imiquimod-induced model of psoriasis

A mouse model of psoriasiform dermatitis caused by topical application of the Toll-like receptor 7 (TLR7) and TLR8 agonist imiquimod. The imiquimod model is relatively easy to perform and, although not a perfect mimic of the human disease, it reflects key immune pathways in psoriasis such as the involvement of the interleukin-23–T helper 17 cell axis.

Group 1 ILCs

A group of innate lymphoid cells (ILCs) — including natural killer cells and a subset of ILCs (ILC1s) — that produce type 1 cytokines such as tumour necrosis factor and interferon-γ, and express the transcription factor T-bet. These cells contribute to immune responses against viruses and intracellular pathogens, as well as to tumour surveillance.

Group 2 ILCs

A subset of innate lymphoid cells (ILCs) that produce type 2 cytokines, such as interleukin-4 and interleukin-13. Their development depends on the transcription factors retinoic acid receptor-related orphan receptor-α and GATA-binding protein 3. These cells contribute to tissue repair and parasite elimination, as well as to the development of asthma and allergy.

Group 3 ILCs

A subset of innate lymphoid cells (ILCs) that mainly reside in the intestinal tract. Their development depends on the transcription factor retinoic acid receptor-related orphan receptor-γt. These cells are thought to regulate the balance between the microbiota and the intestinal immune system. This group of cells includes lymphoid tissue inducer cells (which are involved in the development of lymphoid tissue), natural cytotoxicity triggering receptor (NCR)-expressing ILC3s (which mainly produce IL-22), and NCR-negative ILC3s (which mainly produce IL-17A).

Necroptosis

A programmed form of necrotic cell death mediated by receptor-interacting protein kinase 1 (RIPK1) and RIPK3. It can be induced by death receptors and by TIR-domain-containing adaptor protein inducing interferon-β (TRIF)-dependent Toll-like receptor 3 (TLR3) and TLR4 signalling. Inhibition of caspase 8 activation sensitizes cells to necroptosis.

Linear ubiquitin assembly complex

(LUBAC). A ubiquitin ligase complex composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL1L (haem-oxidized IRP2 ubiquitin ligase 1) and HOIP (HOIL1-interacting protein) that generates linear polyubiquitin chains. LUBAC-mediated linear ubiquitylation of NF-κB essential modulator (NEMO) and other components of the tumour necrosis factor (TNF) receptor 1 signalling pathway regulates cellular responses to TNF.

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DOI

https://doi.org/10.1038/nri3646

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