Bone morphogenetic protein signaling regulates skin inflammation via modulating dendritic cell function

Abstract

Background: Bone morphogenetic proteins (BMPs) are members of the TGF-b family that signal via the BMP receptor (BMPR) signaling cascade, distinct from canonical TGF-b 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 (DCs). Regulatory T (Treg)-cell numbers strongly increase during psoriatic skin inflammation and were recently shown to limit psoriatic skin inflammation. However, the factors mediating Treg-cell accumulation in psoriatic skin currently remain unknown. Objective: We sought to investigate the role of BMP signaling in Treg-cell accumulation in psoriasis. Methods: The following methods were used: immunohistology of patients and healthy controls; ex vivo models of Treg-cell generation in the presence or absence of Langerhans cells; analysis of BMP versus canonical TGF-b signaling in DCs and Treg cells; and modeling of psoriatic skin inflammation in mice lacking the BMPR type 1a in CD11c 1 cells. Results: We here demonstrated a positive correlation between Treg-cell numbers and epidermal BMP7 expression in cutaneous psoriatic lesions and show that unlike Treg cells from healthy skin, a portion of inflammation-associated Treg cells exhibit constitutive-active BMP signaling. We further found

DNA Methylation Patterns in CD8+ T Cells Discern Psoriasis From Psoriatic Arthritis and Correlate With Cutaneous Disease Activity

“…The BMP signaling pathway is an important regulator of epidermal homeostasis, hair follicle growth, melanogenesis and has previously been linked with the pathobiology of psoriasis ( Botchkarev, 2003 ). Notably, Sconocchia et al (2021) recently suggested functional links between BMP signaling and regulatory CD4 + T cell (Treg) accumulation in psoriatic skin lesions. This is further supported by reports of dysregulated BMP-4 expression in psoriatic skin lesions that recover after 16 weeks of treatment with the TNF inhibitor adalimumab ( Di Costanzo et al, 2019 ).…”

“…Indeed, in response to treatment, we identified DMPs previously associated with epithelial cell development, TGF-β, and SMAD pathways. SMAD is a pivotal intracellular effector for TGF-β and BMP signaling ( Dituri et al, 2019 ), both involved in the pathophysiology of psoriasis ( Borek et al, 2020 ; Sconocchia et al, 2021 ).…”

Regulation of the Immune System in Health and Disease by Members of the Bone Morphogenetic Protein Family

“…Treatment of monocyte-derived (mo)DCs with BMP ligands promoted the expression of maturation markers CD80, CD83, and CD86 and promotes IL-8 secretion ( 10 ). Besides increasing the expression of co-stimulatory markers, it was also described to increase the expression of the co-inhibitory markers programmed death-ligand (PD-L1) and PD-L2 ( 11 , 12 ). By inhibiting autocrine BMP signaling during moDC maturation with the small molecule BMP inhibitor dorsomorphin (DM) Martinez et al., could show that this resulted in lower expression of PD-L1 and PD-L2 without impacting the expression of other co-stimulatory markers in a process that is mediated through the IRF-1 transcription factor ( 11 ).…”

“…Functionally, BMP7-LCs secrete higher amounts of pro-inflammatory and anti-inflammatory cytokines in response to bacterial stimuli and possess a greater allostimulatory capacity of CD4 + T cells ( 16 ). Additionally, BMP7-LCs are stronger in promoting regulatory T (Treg) cell differentiation and naïve CD4 + T cells cultured in the presence of BMP7-LCs secrete lower amounts of IL-22 in comparison to naïve CD4 + T cells cultured with TGF-β1-LCs ( 12 ).…”

Immunotherapy as a Turning Point in the Treatment of Acute Myeloid Leukemia

“…Thus, cancer cells may achieve this goal by a complex network of cooperation with immune cells and stromal cells. Then, anti-inflammatory (M2) tumor-associated macrophages (TAMs) are recruited into the tumor while regulatory T cells (Treg) are generated in the presence of anti-inflammatory molecules including the transforming growth factors (TGFs) and bone morphogenetic proteins (BMPs) [ 92 , 93 , 94 , 95 , 96 ]. Importantly, T cell activity can be further inhibited by stimulation of the immune checkpoint axes.…”