No abstract

IL-36 family members are highly expressed in hyperproliferative keratinocytes and play an important role in the pathogenesis of skin diseases such as psoriasis. However, whether and how IL-36 cytokines are induced to promote wound healing remains unknown. Here we showed that skin injury increased the expression of IL-36γ to promote wound healing. Mechanistically, the expression of IL-36γ was induced by RNAs from damaged cells via the activation of toll-like receptor 3 (TLR3) and TIR-domain-containing adapter-inducing IFN-β (TRIF) followed by the induction of a zinc finger protein SLUG to abrogate the inhibitory effect of vitamin D receptor (VDR) on the promoter of IL-36γ gene. IL-36γ acted back on keratinocytes to induce REG3A, which regulated keratinocyte proliferation and differentiation, thus promoting wound re-epithelialization. These observations show that skin injury increases IL-36γ via the activation of TLR3-SLUG-VDR axis and that IL-36γ induces REG3A to promote wound healing. These findings also provide insights into pathways contributing to wound repair.

No abstract

Mechanical force regulates bone density, modeling, and homeostasis. Substantial periosteal bone formation is generated by external mechanical stimuli, yet its mechanism is poorly understood. Here, it is shown that myeloid‐lineage cells differentiate into subgroups and regulate periosteal bone formation in response to mechanical loading. Mechanical loading on tibiae significantly increases the number of periosteal myeloid‐lineage cells and the levels of active transforming growth factor β (TGF‐β), resulting in cortical bone formation. Knockout of Tgfb1 in myeloid‐lineage cells attenuates mechanical loading‐induced periosteal bone formation in mice. Moreover, CD68+F4/80+ macrophages, a subtype of myeloid‐lineage cells, express and activate TGF‐β1 for recruitment of osteoprogenitors. Particularly, mechanical loading induces the differentiation of periosteal CD68+F4/80− myeloid‐lineage cells to the CD68+F4/80+ macrophages via signaling of piezo‐type mechanosensitive ion channel component 1 (Piezo1) for TGF‐β1 secretion. Importantly, CD68+F4/80+ macrophages activate TGF‐β1 by expression and secretion of thrombospondin‐1 (Thbs1). Administration of Thbs1 inhibitor significantly impairs loading‐induced TGF‐β activation and recruitment of osteoprogenitors in the periosteum. The results suggest that periosteal myeloid‐lineage cells respond to mechanical forces and consequently produce and activate TGF‐β1 for periosteal bone formation.

No abstract

Human S100A7 (psoriasin) is highly expressed in psoriasis and other inflammatory diseases; however, the function of S100A7 in wound repair remains largely unknown. Here we demonstrated that skin injury increased the expression of S100A7. Damaged cells from wounded skin induced the expression of S100A7 via the activation of Toll-like receptor 3 (TLR3) followed by the activation of p38 MAPK. S100A7, in turn, acted on keratinocytes to induce the expression of terminal differentiation marker gene loricrin through the activation of p38 MAPK and caspase-1. The differentiation of keratinocytes induced by S100A7 resulted in skin stratification, thus efficiently promoting wound closure. Taken together, our results demonstrate that the activation of TLR3 accelerates wound closure via the induction of S100A7 to induce keratinocyte differentiation. These findings also provide new insights into the development of different forms of treatment with skin wounds.

Bone homeostasis is maintained through a balance of bone formation by osteoblasts and bone resorption by osteoclasts. Ubiquitin-specific proteases (USPs) are involved in regulating bone metabolism by preserving bone formation or antagonizing bone resorption. However, the specific USPs that maintain bone homeostasis by orchestrating bone formation and bone resorption simultaneously are poorly understood. Here, we identified USP26 as a previously unknown regulator of bone homeostasis that coordinates bone formation and resorption. Mechanistically, USP26 stabilizes β-catenin to promote the osteogenic activity of mesenchymal cells (MSCs) and impairs the osteoclastic differentiation of bone myelomonocytes (BMMs) by stabilizing inhibitors of NF-κBα (IκBα). Gain-of-function experiments revealed that Usp26 supplementation significantly increased bone regeneration in bone defects in aged mice and decreased bone loss resulting from ovariectomy. Taken together, these data show the osteoprotective effect of USP26 via the coordination of bone formation and resorption, suggesting that USP26 represents a potential therapeutic target for osteoporosis.

No abstract