Ren Lingyan, Liu Guangjun, Bai Yun, Gu Liling, Wang Yuan, Sun Li
Department of Orthopedics, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province, 550003, China.
Antenatal Diagnosis Centre, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province, 550003, China.
J Mol Med (Berl). 2024 May;102(5):655-665. doi: 10.1007/s00109-024-02422-y. Epub 2024 Mar 4.
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 TNFα Th17 cell responses. In osteoporosis, NLRC3 attenuated TNFα 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 TNFα + 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 TNFα + Th17 cells of RANKL, MIP1α, and MCP1, depending on the T cells. In addition, NLRC3 negatively regulated the Th17 osteoclastogenesis promoting functions via limiting the NF-κB 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. KEY MESSAGES: NLRC3 negatively regulated the Th17 osteoclastogenesis promoting functions via limiting the NF-κB activation. NLRC3 may be the candidate anti-OP therapeutic target.
含CARD结构域的NOD样受体家族成员3（NLRC3）是属于NLR（NOD样受体）家族的细胞内蛋白。NLRC3可负向调节适应性免疫细胞和固有免疫细胞内的炎症信号转导通路。然而，关于NLRC3在骨重塑中的生物学作用仍需进一步研究阐明。在此，我们的研究证明NLRC3通过抑制TNFα Th17细胞反应来预防骨质流失。在骨质疏松症中，NLRC3可减少骨髓中TNFα Th17细胞的积聚。然而，在NLRC3基因敲除的去卵巢（OVX）小鼠中，骨质疏松症（OP）的发展加剧，但不影响骨髓巨噬细胞（BMM）的破骨细胞生成。在本研究中，我们将野生型和NLRC3 CD4细胞转移到Rag1小鼠体内。结果，我们证实了NLRC3在CD4 T细胞中对抑制TNFα+Th17细胞积聚的作用，从而限制了OVX小鼠的骨质流失。同时，NLRC3 CD4 T细胞促进破骨细胞前体和炎性单核细胞募集到OVX小鼠骨髓中。从机制上来说，NLRC3可减少RANKL、MIP1α和MCP1的TNFα+Th17细胞分泌，这依赖于T细胞。此外，NLRC3通过限制NF-κB激活负向调节Th17促进破骨细胞生成的功能。总的来说，本研究认识到NLRC3通过依赖CD4细胞的适应性免疫调节骨量的作用。根据本研究结果，NLRC3可能是抗OP治疗的候选靶点。关键信息：NLRC3通过限制NF-κB激活负向调节Th17促进破骨细胞生成的功能。NLRC3可能是抗OP治疗的候选靶点。
