ILC3 inhibits Osteoclastogenesis and ameliorates Inflammatory Bone Loss in Post-menopausal Osteoporosis

Although the significance of T lymphocytes in maintaining bone homeostasis is well established, the role of innate lymphoid cells (ILCs), the innate counterparts of T cells, in maintaining bone homeostasis is uncertain. In this study, we examined, for the first time, the anti-osteoclastogenic property of ILC3 in vitro. We observed that ILC3 inhibits RANKL-mediated osteoclastogenesis in a cell ratio-dependent manner. We further employed an ovariectomized (ovx) mouse model, which mimics postmenopausal osteoporosis (PMO), to investigate the role of ILC3 in inflammatory bone loss. Notably, our in vivo data unequivocally validate that the ovx mice have a markedly lower frequency of ILC3 in the bone marrow (BM). Furthermore, the temporal-kinetic analysis revealed that alterations in ILC3 cell dynamics and function in the BM are associated with the development and progression of inflammatory bone loss in PMO. Additionally, our in vivo results demonstrate that dysbiosis in PMO drives significant alterations in the frequency of ILC3 subsets by promoting the expansion of IL-17-producing Nkp46- ILC3 and inhibiting the development of IL-22-producing Nkp46+ ILC3. Moreover, T-bet+ ILC3s are significantly increased in ovariectomized (ovx) mice. Altogether, the present study for the first time, reports the critical role of dysregulated ILC3 in the progression of PMO and offers a novel immunotherapeutic approach targeting ILC3 for treating and managing PMO. Graphical abstractPMO is associated with leaky gut and dysbiosis, which leads to a deficiency of SCFAs in the ovx mice. Dysbiosis in ovx mice disturbs the homeostatic balance of the ILC3 with an increase in IL-17-producing ILC3 and a decrease in IL-22-producing ILC3. Further Tbet expression is enhanced in the ILC3 of the ovx mice, which is associated with disease pathogenesis. Additionally, IL-2 expression is decreased in the ILC3 of the ovx mice. Decreased expression of ILC3 migratory molecules reduced the migration of ILC3 in bone marrow. ILC3 inhibits osteoclast differentiation. However, in the case of ovx mice, ILC3 are compromised and promote osteoclastogenesis. O_FIG O_LINKSMALLFIG WIDTH=154 HEIGHT=200 SRC="FIGDIR/small/677486v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@10543ccorg.highwire.dtl.DTLVardef@a6452dorg.highwire.dtl.DTLVardef@798f8org.highwire.dtl.DTLVardef@cc026c_HPS_FORMAT_FIGEXP M_FIG C_FIG