The Mechanisms By Which Interleukin-17D Regulates Innate Immune Memory In Keratinocytes

Psoriasis relapse in the same locations is always a condundrum.So far,memory-likeγδT cells or tissue-resident memory T cells are considered as the main drivers of psoriasis relapsing.However,these memory cells not just reside in the site of the lesion,but also migrate to other parts of the skin.Therefore,they are probably not the only reason that causes psoriasis relapsing in the same location.Besides memory T cells,basal keratinocytes（KCs）have been show to have the ability to aquire innate immune memory.However,the underlying mechanisms by which KCs acquire innate immune memory and whether KCs with innate immune memory would be involved in the relapse of psoriasis remain unknown.To address these questions,we first examined whether the inflammatory cytokines highly expressed in psoriatic lesions could induce innate memory of KCs.We stimulated KCs with a panel of cytokines known to highly expressed in psoriatic lesions and detect the level of H3K4me3,a histone modification that marks innate immune memory.We found that IL-1β,IL-36γ,IL-17A,IL-17D,IL-17E and IL-17F increased the level of H3K4me3 in KCs.Next,we used poly（I:C）as a secondary stimulus to stimulated KCs which originally stimulated by these cytokines,and measured innate immune memory by detecting the expressing of poly（I:C）-induced-IL-36γ.It was found that IL-17D induced innate immune memory significantly.Moreover,histone methyltransferase inhibitor MTA inhibited IL-17D-induced H3K4me3 and the expression of IL-36γinduced by poly（I:C）as second stimulation.CHIP assay further confirmed that IL-17D increased the enrichment of H3K4me3 on IL-36γpromoter.Furthermore,the level of H3K4me3 was lower in Il17d^-/-psoriatic mice compared to WT controls.Next we explore the mechanisms by which IL-17D regulated innate immune memory of KCs.Given that glucose metabolism is involved in H3K4me3-mediated innate immune memory in macrophages,we hypothesized that IL-17D might induce innate immune memory of KCs through glucose metabolism.To address this,we isolated KCs from WT and Il17d^-/-mice and showed that the deficiency of Il17d in keratinocytes led to decreased glucose metabolism and amino acid metabolism,that is,Il17d^-/-keratinocytes had less production of pyruvate,lactate,and glutamine which also involves in glucose metabolism.Furthermore,the glucose metabolism inhibitor 2-DG inhibited IL-17D-indued H3K4me3 and innate immune memory in KCs.Notably,among these metabolites regulated by IL-17D,we found that only lactate,a production of glycolysis,was increased in lesional skin of psoriasis compared to normal skin.We thereby further determined whether IL-17D-indcued innate immune memory of KCs would be dependent on lactate.KCs stimulated by lactate showed increased H3K4me3and innate immune memory,whereas the inhibitor of lactate dehydrogenase A（LDHA）oxamate impaired lactate production and innate immune memory induced by IL-17D in KCs.These results suggest that IL-17D induces LDHA to promote lactate production,thereby modulating H3K4me3 and innate immune memory of KCs.In summary,our study demonstrates that IL-17D promotes the production of lactate by LDHA,and the increased lactate induces innate immune memory in KCs by increasing H3K4me3,which provides new insighits into the relapse of psoriasis.