Abstract
Innate lymphoid cells (ILCs) comprise a heterogeneous population of immune cells that maintain barrier function and can initiate a protective or pathological immune response upon infection. Here we show the involvement of IL-17A-producing ILCs in microbiota-driven immunopathology in cutaneous leishmaniasis. IL-17A-producing ILCs were RORγt+ and were enriched in Leishmania major infected skin, and topical colonization with Staphylococcus epidermidis before L. major infection exacerbated the skin inflammatory responses and IL-17A-producing RORγt+ ILC accumulation without impacting type 1 immune responses. IL-17A responses in ILCs were directed by Batf3 dependent CD103+ dendritic cells and IL-23. Moreover, experiments using Rag1-/- mice established that IL-17A+ ILCs were sufficient in driving the inflammatory responses as depletion of ILCs or neutralization of IL-17A diminished the microbiota mediated immunopathology. Taken together, this study indicates that the skin microbiota promotes RORγt+ IL-17A-producing ILCs, which augment the skin inflammation in cutaneous leishmaniasis.
Highlights
Cutaneous leishmaniasis includes a spectrum of diseases ranging from a single ulcerative lesion to severe metastatic lesions, and the magnitude of the disease is often influenced by factors that are independent from the parasite burden
While the microbiota driven IL-17A–secreting Innate lymphoid cells (ILCs) mediated inflammatory response was independent of the parasite burden and a type 1 immune responses, it required stimulation of Batf3-dependent skin dendritic cells, production of IL-23 and the presence of neutrophils
IL-17 has been shown to play an important role in mediating inflammation in cutaneous leishmaniasis [7,8,22] and while Th17 cells are a source of IL-17, it is possible that IL-17 produced by ILCs present in skin could contribute to immunopathology
Summary
Cutaneous leishmaniasis includes a spectrum of diseases ranging from a single ulcerative lesion to severe metastatic lesions [1]. While control of these intracellular parasites is dependent upon the production of IFN-γ by CD4+ T cells, the magnitude of the disease is often influenced by factors other than the parasite burden. Using a combination of murine models and human studies we and others have shown that the skin microbiome enhances IL-1β and IL-17A production and contributes to increased pathology in cutaneous leishmaniasis [9,11,12]. While the role of T cells in promoting an increased inflammatory response is well established [1], whether innate cells initiate and/or amplify a pathogenic response in leishmaniasis is unknown
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