Bone morphogenetic protein signaling regulates skin inflammation via modulating dendritic cell function
2020
Abstract Background Bone morphogenetic proteins (BMPs) are members of the TGF-β family that signal via the BMP receptor (BMPR) signaling cascade, distinct from canonical TGF-β signaling. BMP downstream signaling is strongly induced within epidermal keratinocytes in cutaneous psoriatic lesions and BMP7 instructs monocytic cells to acquire characteristics of psoriasis-associated Langerhans dendritic cells (LCs). Regulatory T cells (Treg) numbers strongly increase during psoriatic skin inflammation and were recently shown to limit psoriatic skin inflammation. However, the factors mediating Treg accumulation in psoriatic skin currently remain unknown. Objective This study sought to investigate the role of BMP signaling in Treg accumulation in psoriasis. Methods Immunohistology of patients and healthy controls. Ex vivo models of Treg generation in the presence or absence of LCs. Analysis of BMP vs canonical TGF-β signaling in DCs and Tregs. Modeling of psoriatic skin inflammation in mice lacking the BMP receptor type 1a in CD11c+ cells. Results We here demonstrated a positive correlation between Treg numbers and epidermal BMP7 expression in cutaneous psoriatic lesions and show that unlike Tregs from healthy skin, a portion of inflammation-associated Tregs exhibit constitutive-active BMP signaling. We further found that BMPR signaling licenses inflammation-associated LC/DC to gain an enhanced capacity to promote Tregs via BMPR-mediated CD25 induction and that this effect is associated with reduced skin inflammation. Conclusions Psoriatic lesions are marked by constitutive high BMP7/BMPR signaling in keratinocytes, which instructs inflammatory DCs to gain enhanced Treg stimulatory activity. Locally secreted BMP7 can directly promote Treg generation through the BMP signaling cascade.
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