NLRC3 attenuates osteoclastogenesis by limiting TNFα⁺ Th17 cell response in osteoporosis

NOD-like receptor family CARD domain containing 3 (NLRC3) is the intracellular protein belonging to NLR (NOD-like receptor) family. NLRC3 can negatively regulate inflammatory signal transduction pathways within the adaptive and innate immunocytes. However, studies need to elucidate the biological role of NLRC3 in bone remodeling. Herein, our study proved that NLRC3 prevents bone loss by inhibiting TNF alpha(+) Th17 cell responses. In osteoporosis, NLRC3 attenuated TNF alpha(+) Th17 cell accumulation in the bone marrow. However, osteoporosis (OP) development was aggravated without affecting bone marrow macrophage (BMM) osteoclastogenesis in NLRC3-deficient ovariectomized (OVX) mice. In this study, we transferred the wild-type and NLRC3(-/-) CD4(+) cells into Rag1(-/-) mice. Consequently, we evidenced the effects of NLRC3 in CD4(+) T cells on inhibiting the accumulation of TNF alpha + Th17 cells, thus restricting bone loss in the OVX mice. Simultaneously, NLRC3(-/-) CD4(+) T cells promoted the recruitment of osteoclast precursors and inflammatory monocytes into the OVX mouse bone marrow. Mechanism-wise, NLRC3 reduced the secretion of TNF alpha + Th17 cells of RANKL, MIP1 alpha, and MCP1, depending on the T cells. In addition, NLRC3 negatively regulated the Th17 osteoclastogenesis promoting functions via limiting the NF-kappa B activation. Collectively, this study appreciated the effect of NLRC3 on modulating bone mass via adaptive immunity depending on CD4(+) cells. According to findings of this study, NLRC3 may be the candidate anti-OP therapeutic target.