Key Points
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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.
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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.
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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.
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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.
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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.
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.
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References
Nestle, F. O., Di Meglio, P., Qin, J. Z. & Nickoloff, B. J. Skin immune sentinels in health and disease. Nature Rev. Immunol. 9, 679–691 (2009).
Di Meglio, P., Perera, G. K. & Nestle, F. O. The multitasking organ: recent insights into skin immune function. Immunity 35, 857–869 (2011).
Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nature Immunol. 7, 265–273 (2006).
Hoeffel, G. et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167–1181 (2012).
Greter, M. et al. Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37, 1050–1060 (2012).
Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nature Immunol. 13, 753–760 (2012).
Nagao, K. et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nature Immunol. 13, 744–752 (2012).
Tamoutounour, S. et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39, 925–938 (2013). A comprehensive analysis of DCs and macrophages in the skin, which provides a clear road map to distinguish different subsets.
Tussiwand, R. et al. Compensatory dendritic cell development mediated by BATF-IRF interactions. Nature 490, 502–507 (2012). A description of the key transcriptional regulators in DC lineage development.
Schraml, B. U. et al. Genetic tracing via DNGR-1 expression history defines dendritic cells as a hematopoietic lineage. Cell 154, 843–858 (2013).
Igyarto, B. Z. et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35, 260–272 (2011).
Stoitzner, P. et al. Langerhans cells cross-present antigen derived from skin. Proc. Natl Acad. Sci. USA 103, 7783–7788 (2006).
Igyarto, B. Z. & Kaplan, D. H. Antigen presentation by Langerhans cells. Curr. Opin. Immunol. 25, 115–119 (2013).
Gao, Y. et al. Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity 39, 722–732 (2013).
Kumamoto, Y. et al. CD301b+ dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 39, 733–743 (2013). References 14 and 15 identify the key cells and transcription factors that are involved in T H 2 cell-dependent immunity in the skin.
Flutter, B. & Nestle, F. O. What on “irf” is this gene 4? Irf4 transcription-factor-dependent dendritic cells are required for T helper 2 cell responses in murine skin. Immunity 39, 625–627 (2013).
Abram, C. L., Roberge, G. L., Pao, L. I., Neel, B. G. & Lowell, C. A. Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice. Immunity 38, 489–501 (2013). This paper shows that exaggerated TLR signalling in CD11c+ DCs causes an autoimmune phenotype in mice that resembles systemic lupus erythematosus in humans.
Idoyaga, J. et al. Specialized role of migratory dendritic cells in peripheral tolerance induction. J. Clin. Invest. 123, 844–854 (2013). This study provides evidence that targeting DCs might be a promising approach for future immunomodulatory therapy of autoimmune disease.
Serbina, N. V., Salazar-Mather, T. P., Biron, C. A., Kuziel, W. A. & Pamer, E. G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).
Wohn, C. et al. Langerinneg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice. Proc. Natl Acad. Sci. USA 110, 10723–10728 (2013).
Lowes, M. A. et al. Increase in TNF-α and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc. Natl Acad. Sci. USA 102, 19057–19062 (2005).
Wang, C. Q. et al. Th17 cells and activated dendritic cells are increased in vitiligo lesions. PLoS ONE 6, e18907 (2011).
Klechevsky, E. et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity 29, 497–510 (2008).
Romano, E. et al. Human Langerhans cells use an IL-15R-α/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1. Blood 119, 5182–5190 (2012).
Seneschal, J., Clark, R. A., Gehad, A., Baecher-Allan, C. M. & Kupper, T. S. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36, 873–884 (2012).
Gunther, C., Starke, J., Zimmermann, N. & Schakel, K. Human 6-sulfo LacNAc (slan) dendritic cells are a major population of dermal dendritic cells in steady state and inflammation. Clin. Exp. Dermatol. 37, 169–176 (2012).
Nestle, F. O., Zheng, X. G., Thompson, C. B., Turka, L. A. & Nickoloff, B. J. Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J. Immunol. 151, 6535–6545 (1993).
Chu, C. C. et al. Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation. J. Exp. Med. 209, 935–945 (2012). This study identifies a key regulatory DC population in human skin that is characterized by the production of IL-10.
Haniffa, M. et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity 37, 60–73 (2012).
Chu, C. C., Di Meglio, P. & Nestle, F. O. Harnessing dendritic cells in inflammatory skin diseases. Semin. Immunol. 23, 28–41 (2011).
Wollenberg, A., Kraft, S., Hanau, D. & Bieber, T. Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J. Invest. Dermatol. 106, 446–453 (1996).
Gilliet, M., Cao, W. & Liu, Y. J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nature Rev. Immunol. 8, 594–606 (2008).
Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med. 202, 135–143 (2005).
Ronnblom, L. & Pascual, V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus 17, 394–399 (2008).
Guiducci, C. et al. Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J. Exp. Med. 207, 2931–2942 (2010).
Flutter, B. & Nestle, F. O. TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis. Eur. J. Immunol. 43, 3138–3146 (2013).
Sisirak, V. et al. CCR6/CCR10-mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues. Blood 118, 5130–5140 (2011).
Drobits, B. et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J. Clin. Invest. 122, 575–585 (2012).
Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011).
Cain, D. W. et al. Identification of a tissue-specific, C/EBPβ-dependent pathway of differentiation for murine peritoneal macrophages. J. Immunol. 191, 4665–4675 (2013).
Von Stebut, E. Immunology of cutaneous leishmaniasis: the role of mast cells, phagocytes and dendritic cells for protective immunity. Eur. J. Dermatol. 17, 115–122 (2007).
Jakubzick, C. et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39, 599–610 (2013).
Zigmond, E. et al. Ly6Chi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37, 1076–1090 (2012).
Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008).
Fuentes-Duculan, J. et al. A subpopulation of CD163-positive macrophages is classically activated in psoriasis. J. Invest. Dermatol. 130, 2412–2422 (2010).
Sugaya, M. et al. Association of the numbers of CD163+ cells in lesional skin and serum levels of soluble CD163 with disease progression of cutaneous T cell lymphoma. J. Dermatol. Sci. 68, 45–51 (2012).
Wang, H. et al. Activated macrophages are essential in a murine model for T cell-mediated chronic psoriasiform skin inflammation. J. Clin. Invest. 116, 2105–2114 (2006).
Stratis, A. et al. Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation. J. Clin. Invest. 116, 2094–2104 (2006).
Meng, G., Zhang, F., Fuss, I., Kitani, A. & Strober, W. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity 30, 860–874 (2009).
Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A. & Locati, M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 229, 176–185 (2013).
Kataru, R. P. et al. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113, 5650–5659 (2009).
Egawa, M. et al. Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin-4. Immunity 38, 570–580 (2013). This study shows that pro-inflammatory M1 monocytes can acquire an anti-inflammatory M2 phenotype in the skin under the influence of basophil-derived IL-4.
Chiang, N. et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524–528 (2012).
St John, A. L. et al. Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance. Proc. Natl Acad. Sci. USA 108, 9190–9195 (2011).
Nakamura, Y. et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 503, 397–401 (2013). This study shows that δ-toxin from S. aureus directly stimulates mast cell degranulation, thus triggering cutaneous allergic responses.
Nakamura, Y. et al. Critical role for mast cells in interleukin-1β-driven skin inflammation associated with an activating mutation in the Nlrp3 protein. Immunity 37, 85–95 (2012). This study shows that mast cells are required but are not sufficient for the development of disease in a mouse model of MWS.
Hershko, A. Y. et al. Mast cell interleukin-2 production contributes to suppression of chronic allergic dermatitis. Immunity 35, 562–571 (2011).
Streilein, J. W. Skin-associated lymphoid tissues (SALT): origins and functions. J. Invest. Dermatol. 80, 12s–16s (1983).
Kupper, T. S. & Fuhlbrigge, R. C. Immune surveillance in the skin: mechanisms and clinical consequences. Nature Rev. Immunol. 4, 211–222 (2004).
Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-α. J. Exp. Med. 199, 731–736 (2004).
Boyman, O., Conrad, C., Tonel, G., Gilliet, M. & Nestle, F. O. The pathogenic role of tissue-resident immune cells in psoriasis. Trends Immunol. 28, 51–57 (2007).
Conrad, C. et al. α1β1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nature Med. 13, 836–842 (2007).
Clark, R. A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006).
Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nature Immunol. 10, 524–530 (2009).
Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010).
Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).
Mackay, L. K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc. Natl Acad. Sci. USA 109, 7037–7042 (2012).
Shin, H. & Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463–467 (2012).
Liu, L. et al. Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity. Nature Med. 16, 224–227 (2010).
Jiang, X. et al. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483, 227–231 (2012).
Teijaro, J. R. et al. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510–5514 (2011).
Clark, R. A. et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Transl Med. 4, 117ra7 (2012).
Rosenblum, M. D. et al. Response to self antigen imprints regulatory memory in tissues. Nature 480, 538–542 (2011). This study is the first to demonstrate the existence of skin-resident memory T cells that protect from potentially damaging tissue autoimmunity.
Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nature Rev. Immunol. 13, 88–100 (2013).
Barbee, S. D. et al. Skint-1 is a highly specific, unique selecting component for epidermal T cells. Proc. Natl Acad. Sci. USA 108, 3330–3335 (2011).
Silva-Santos, B. Promoting angiogenesis within the tumor microenvironment: the secret life of murine lymphoid IL-17-producing γδ T cells. Eur. J. Immunol. 40, 1873–1876 (2010).
Sumaria, N. et al. Cutaneous immunosurveillance by self-renewing dermal γδ T cells. J. Exp. Med. 208, 505–518 (2011).
Gray, E. E., Suzuki, K. & Cyster, J. G. Cutting edge: identification of a motile IL-17-producing γδ T cell population in the dermis. J. Immunol. 186, 6091–6095 (2011).
Becher, B. & Pantelyushin, S. Hiding under the skin: interleukin-17-producing γδ T cells go under the skin? Nature Med. 18, 1748–1750 (2012).
Cai, Y. et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35, 596–610 (2011).
Pantelyushin, S. et al. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J. Clin. Invest. 122, 2252–2256 (2012).
Gray, E. E. et al. Deficiency in IL-17-committed Vγ4+ γδ T cells in a spontaneous Sox13-mutant CD45.1+ congenic mouse substrain provides protection from dermatitis. Nature Immunol. 14, 584–592 (2013).
Van Belle, A. B. et al. IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice. J. Immunol. 188, 462–469 (2012).
Bouchaud, G. et al. Epidermal IL-15Rα acts as an endogenous antagonist of psoriasiform inflammation in mouse and man. J. Exp. Med. 210, 2105–2117 (2013).
Mabuchi, T. et al. CCR6 is required for epidermal trafficking of γδ-T cells in an IL-23-induced model of psoriasiform dermatitis. J. Invest. Dermatol. 133, 164–171 (2013).
Tortola, L. et al. Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J. Clin. Invest. 122, 3965–3976 (2012).
Gatzka, M. et al. Reduction of CD18 promotes expansion of inflammatory γδ T cells collaborating with CD4+ T cells in chronic murine psoriasiform dermatitis. J. Immunol. 191, 5477–5488 (2013).
Laggner, U. et al. Identification of a novel proinflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis. J. Immunol. 187, 2783–2793 (2011).
Witherden, D. A. & Havran, W. L. Crosstalk between intraepithelial γδ T cells and epithelial cells. J. Leukocyte Biol. 94, 69–76 (2013).
Witherden, D. A. et al. The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal γδ T cell function. Immunity 37, 314–325 (2012).
Gay, D. et al. Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding. Nature Med. 19, 916–923 (2013).
Spits, H. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nature Rev. Immunol. 13, 145–149 (2013).
Villanova, F. et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J. Invest. Dermatol. 134, 984–991 (2014).
Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nature Immunol. 14, 564–573 (2013).
Kim, B. S. et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci. Transl Med. 5, 170ra16 (2013).
Salimi, M. et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J. Exp. Med. 210, 2939–2950 (2013).
Lizzul, P. F. et al. Differential expression of phosphorylated NF-κB/RelA in normal and psoriatic epidermis and downregulation of NF-κB in response to treatment with etanercept. J. Invest. Dermatol. 124, 1275–1283 (2005).
Sano, S. et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nature Med. 11, 43–49 (2005).
Takahashi, H. et al. Extracellular regulated kinase and c-Jun N-terminal kinase are activated in psoriatic involved epidermis. J. Dermatol. Sci. 30, 94–99 (2002).
Zenz, R. et al. Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis Res. Ther. 10, 201 (2008).
Zenz, R. et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437, 369–375 (2005).
Guinea-Viniegra, J. et al. TNF-α shedding and epidermal inflammation are controlled by Jun proteins. Genes Dev. 23, 2663–2674 (2009).
Chiang, M. F. et al. Inducible deletion of the Blimp-1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice. Proc. Natl Acad. Sci. USA 110, 6476–6481 (2013).
Briso, E. M. et al. Inflammation-mediated skin tumorigenesis induced by epidermal c-Fos. Genes Dev. 27, 1959–1973 (2013).
Uto-Konomi, A. et al. Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines. PLoS ONE 7, e40343 (2012).
Reich, K. et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 366, 1367–1374 (2005).
Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002).
Lind, M. H. et al. Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-κB inhibition. Proc. Natl Acad. Sci. USA 101, 4972–4977 (2004).
Kumari, S. et al. Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice. Immunity 39, 899–911 (2013). This study shows that keratinocyte-intrinsic TNFR1 signalling drives psoriasis-like skin inflammation by inducing IL-24 expression.
Bonnet, M. C. et al. The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35, 572–582 (2011).
He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009).
Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).
Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).
Weinlich, R. et al. Protective roles for caspase-8 and cFLIP in adult homeostasis. Cell Rep. 5, 340–348 (2013).
Panayotova-Dimitrova, D. et al. cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep. 5, 397–408 (2013).
Nenci, A. et al. Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling. Hum. Mol. Genet. 15, 531–542 (2006).
Omori, E. et al. TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis. J. Biol. Chem. 281, 19610–19617 (2006).
Omori, E., Morioka, S., Matsumoto, K. & Ninomiya-Tsuji, J. TAK1 regulates reactive oxygen species and cell death in keratinocytes, which is essential for skin integrity. J. Biol. Chem. 283, 26161–26168 (2008).
Gerlach, B. et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591–596 (2011).
Ikeda, F. et al. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471, 637–641 (2011).
Tokunaga, F. et al. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471, 633–636 (2011).
Kajino-Sakamoto, R. et al. Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis. J. Immunol. 181, 1143–1152 (2008).
Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).
Welz, P. S. et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330–334 (2011). References 110 and 124 show that epithelial-specific ablation triggers RIPK3-dependent epithelial cell necroptosis and inflammation in the skin and the intestine.
Wittkopf, N. et al. Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. Gastroenterology 145, 1369–1379 (2013).
Piao, X. et al. c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. Sci. Signal. 5, ra93 (2012).
Krachler, A. M., Woolery, A. R. & Orth, K. Manipulation of kinase signaling by bacterial pathogens. J. Cell Biol. 195, 1083–1092 (2011).
Gilmore, T. D. & Herscovitch, M. Inhibitors of NF-κB signaling: 785 and counting. Oncogene 25, 6887–6899 (2006).
Mocarski, E. S., Upton, J. W. & Kaiser, W. J. Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways. Nature Rev. Immunol. 12, 79–88 (2012).
Li, S. et al. Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains. Nature 501, 242–246 (2013).
Pearson, J. S. et al. A type III effector antagonizes death receptor signalling during bacterial gut infection. Nature 501, 247–251 (2013).
Findley, K. et al. Topographic diversity of fungal and bacterial communities in human skin. Nature 498, 367–370 (2013).
Grice, E. A. et al. Topographical and temporal diversity of the human skin microbiome. Science 324, 1190–1192 (2009).
Gallo, R. L. & Hooper, L. V. Epithelial antimicrobial defence of the skin and intestine. Nature Rev. Immunol. 12, 503–516 (2012).
Scholz, F., Badgley, B. D., Sadowsky, M. J. & Kaplan, D. H. Immune mediated shaping of microflora community composition depends on barrier site. PLoS ONE 9, e84019 (2014).
Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012). This study shows that a commensal skin bacterium, S. epidermidis , controls dermis-resident T cell function and immunity to L. major by activating an IL-1-dependent immune response.
Rudikoff, D. & Lebwohl, M. Atopic dermatitis. Lancet 351, 1715–1721 (1998).
Myles, I. A. et al. Signaling via the IL-20 receptor inhibits cutaneous production of IL-1β and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus. Nature Immunol. 14, 804–811 (2013).
Miller, L. S. et al. MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 24, 79–91 (2006).
Cho, J. S. et al. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J. Clin. Invest. 120, 1762–1773 (2010).
Perera, G. K. et al. Integrative biology approach identifies cytokine targeting strategies for psoriasis. Sci. Transl Med. 6, 223ra22 (2014).
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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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
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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
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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
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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
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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
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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
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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
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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
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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
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(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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Pasparakis, M., Haase, I. & Nestle, F. Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol 14, 289–301 (2014). https://doi.org/10.1038/nri3646
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DOI: https://doi.org/10.1038/nri3646
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