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Tuning of skin immunity by skin commensal bacteria Evaluation of: Naik S, Bouladoux N, Wilhelm C et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012). Most analyses of commensal microbiota have been directed toward the gut microbiota and its role in the development of the intestinal immune system, and in regulating the immune response at sites distant from the gut, including the joints or CNS. However, very little is known about how other niches of commensal microbiota affect local immunity and whether they are influenced by the gut microbiota. The current paper reveals that skin commensals are required for the development of protective immunity against a cutaneous pathogen. This immune response driven by skin commensals occurs independently of the gut microbiota and is mediated by MyD88 and IL‑1 signaling that promotes protective effector T-cell responses. KEYWORDS: infection n microbiome n microbiota n regional immunity n skin n vaccine
The importance of the gut microbiota in the development of the immune response and inflammatory diseases is well established. Indeed, gut commensals have been shown to direct maturation of the host immune system [1] and to drive Treg, Th1 and Th17 cell development [2–4]. In the past several years, various reports have shown that an imbalance in gut microbiota that favors induction of effector T cells versus Tregs correlates with autoimmune/inflammatory disease development. The presence of segmented filamentous bacteria in the murine gut is associated with the development of Th17 cells and Th17-mediated autoimmune diseases such as colitis, arthritis and experimental autoimmune encephalomyelitis [5–7]. By contrast, Clostridium leptum and coccoides bacteria have been associated with the induction of Tregs and resistance to dextrum sodium sulfate-induced colitis in mice [2]. However, little is known about the role that commensals in niches other than the gut play in local immunity and disease development. More specifically, we do not know whether commensal bacteria in cutaneous sites, for example, control the immune response in the skin. In a seminal paper published in Science, Naik et al. report for the first time that commensal bacteria in the skin play an important role in the development of local immunity in the skin and the subsequent protection against cutaneous infection [8].
Summary of methods & results The authors use germ-free (GF) and specific pathogen-free (SPF) mice to demonstrate the
importance of skin commensals in the development of cutaneous immunity at the site. They found that the absence of skin commensals in GF mice led to a decreased production of IFNg by ab T cells and IL‑17A by ab and gd T cells, but an increase in Foxp3+ Tregs in the skin compared with SPF mice. When SPF mice received oral antibiotics, the gut, but not the skin, commensal composition was affected, correlating with reduced inflammatory cytokine (IL‑17A and IFNg) production in the gut, but not the skin. Furthermore, application of the skin commensal, Staphylococcus epidermidis to the skin of GF mice restored the ability of T-cell receptor b+ (TCRb+) T cells to produce IL‑17A in the skin, but not the gut. By contrast, oral administration of the gut commensal – segmented filamentous bacteria – to GF mice had no impact on effector cytokine production in the skin. These data indicate that only the skin, not the gut, microbiota controls the homeostasis of effector T cells and Tregs in the skin. The ability of skin commensal bacteria to control immunity against cutaneous pathogens was next assessed. The GF mice intradermally infected with Leishmania major exhibited smaller lesions with reduced edema and necrosis, which correlated with reduced numbers of cutaneous IFNg- and TNFa-producing T cells, and greater recovery of the L. major parasite from the lesions compared with SPF mice. However, when S. epidermidis (the skin commensal) was concomitantly administered to GF mice, the size of the skin lesions, amount of necrosis and
10.2217/IMT.12.140 © 2013 Future Medicine Ltd
Immunotherapy (2013) 5(1), 23–25
Michele M Kosiewicz1, Arin L Zirnheld1 & Pascale Alard1* Department of Microbiology & Immunology, University of Louisville, HSC, Louisville, KY 40202, USA *Author for correspondence: Tel.: +1 502 852 5364
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production of IFNg by TCRb+ cells increased significantly, and the number of L. major parasites recovered from the lesions was similar to SPF mice, indicating that colonization of the skin with S. epidermidis could restore the induction of an inflammatory response against the cutaneous pathogen L. major. Lastly, the adaptor molecules and pro inflammatory cytokines that were involved in the induction of skin commensal-mediated immunity were investigated by using knockout mice and antagonist treatment strategies. Both MyD88 and IL‑1R1 knockout mice exhibited reduced IL‑17A production by TCRb+ cells in the skin, but not the gut, compared with wildtype mice. Moreover, irradiated wild-type mice reconstituted with MyD88 knockout bone marrow cells exhibited a reduction in IFNg and IL‑17A production by TCRab+ cells in the skin, but not the gut. Furthermore, IL‑1 was identified as the key cytokine driving the IL‑17A-mediated inflammatory response in the skin. IL‑1a and IL‑1b, but not IL‑6, stimulated skin lymphocytes to release IL‑17A. IL‑1a production by cutaneous cells was significantly reduced in GF mice compared with SPF mice, but was restored following application of S. epidermidis. Upon L. major infection, MyD88 and IL‑1R1 knockout mice both exhibited reduced numbers of IFNgproducing T cells compared with infected wildtype mice, and this was also true in wild-type mice treated with IL-1R antagonists. Finally, IL-1R antagonists abrogated the restoration of IL‑17A-producing T cells and L. major-specific IFNg-producing T cells in GF mice receiving an application of S. epidermidis. Taken together, these data suggest that skin commensals promote the optimal inflammatory T-cell response that is required to keep skin pathogens at bay via a mechanism involving MyD88-driven IL‑1 signaling.
Discussion This report is the first to show that resident commensal bacteria control the compartment alization of the immune response in the skin [8]. As in the gut, commensals in the skin control the local immune response. However, in the skin, IL‑1, not IL‑6, is crucial for the generation of IL-17-producing T cells. Interestingly, altering the gut microbiota had no effect on the cutaneous immune response, and conversely, monocolonizing the skin with a skin commensal had no impact on the gut immune response [8]. Other commensal bacteria residing in regional niches have been shown to control infection 24
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at those sites. In a recent study, Lactobacillus sakei, a sinus commensal, was found to prevent Corynebacterium tuberculostearicum-mediated sinusitis [9], however, the immune response in the sinus was not examined in that study. The concept that resident commensal bacteria can influence tissue-specific immunity may have many implications for our modern lifestyle. It may explain the increase in autoimmune and allergic diseases observed in industrialized countries. The excessive use of antibacterial soaps and antibiotics is likely to be detrimental to the optimal development of immunity at various sites other than the gut; for example, alteration in the skin microbiota observed in psoriasis patients compared with normal individuals [10] may contribute to the development of psoriasis, which can be triggered by infection and involves IL‑1 signaling and Th17 cells [11]. The absence of the local microbiota and, hence, its effect on tissuespecific immunity, most likely contributes to the enhanced incidence of opportunistic bacterial and fungal infections observed at various mucosal sites following antibiotic/antibacterial treatments. By altering local microbiota, such treatments may affect local immunity resulting in potential pathogen invasion. These findings also have implications for the development of vaccines and therapies targeting pathogens in specific tissues. As shown in this study, IL‑1 and MyD88 signaling play an important role in the skin, but not gut, immunity [8]. When attempting to manipulate the immune system via vaccination or therapies, it may be important to consider which type of tissue is being targeted to elicit an optimal immune response at the site. Future vaccine design should, therefore, take into consideration the local microbiota, especially the signaling molecules involved and the subsequent local immunity generated. For this reason, the route of immunization and the adjuvant type will certainly be important parameters to consider. More recently, probiotics have been evaluated for their ability to improve the efficacy of viral vaccines, for example, influenza vaccines [12]. One possible way to enhance the adjuvanticity of vaccines could be to harness the adjuvant effect of the local microbiota in order to target the local immune response more specifically and effectively. The development of intranasal and intradermal vaccines is underway and should achieve those goals.
Future perspective This seminal paper by Naik et al. demonstrates that resident commensal bacteria in the future science group
Tuning of skin immunity by skin commensal bacteria
skin control the local immune response, as previously described, in the gut. Whether this concept applies to all mucosal sites and the role that local microbiota play in various diseases, remains to be determined. This study, therefore, provides compelling reasons for further ana lysis of the microbiome not only in the gut, but at other sites and in healthy compared with sick individuals, as proposed by the Human Microbiome Project launched in 2008. These analyses can provide further information on how changes in resident commensal composition can lead to alterations in the immune response and subsequently, pathogenesis. In addition, they can aid in the design of novel therapies aimed at re-establishing a balanced local microbiota. It is very likely that customized therapies, such
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as recolonization of specific sites with particular beneficial commensals, will be the way of the future. Furthermore, fungal and viral microbiota should also be investigated, since these types of microorganisms interact with the immune system and influence heath and disease as well [13,14]. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Executive summary This paper reveals a crucial role for the skin microbiota in the development of local skin immunity and protection against cutaneous pathogens. This compartmentalization of the local immunity by skin commensals is mediated by specific signaling pathways and should be taken into consideration for vaccine design. Microbiome analysis must be extended to sites other than the gut. bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflamm. Bowel Dis. 13, 1202–1211 (2007).
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