NLRP12 provides a critical checkpoint for osteoclast differentiation

Abstract

The alternative or noncanonical nuclear factor kappa B (NF-κB) pathway regulates the osteoclast (OC) response to receptor activator of nuclear factor kappa B ligand (RANKL) and thus bone metabolism. Although several lines of evidence support the emerging concept that nucleotide-binding leucine-rich repeat and pyrin domain-containing receptor 12 (NLRP12) impedes alternative NF-κB activation in innate immune cells, a functional role for NLRP12 outside an inflammatory disease model has yet to be reported. Our study demonstrates that NLRP12 has a protective role in bone via suppression of alternative NF-κB-induced osteoclastogenesis and is down-modulated in response to osteoclastogenic stimuli. Here, we show that retroviral overexpression of NLRP12 suppressed RelB nuclear translocation and OC formation. Conversely, genetic ablation of NLRP12 promoted NIK stabilization, RelB nuclear translocation, and increased osteoclastogenesis in vitro. Using radiation chimeras, we demonstrated these in vitro observations dovetail with our in vivo findings that NLRP12 deficiency leads to enhanced OC numbers accompanied by a significant decline in bone mass under physiological conditions. Consistent with the basal bone phenotype, we also observed an enhanced osteolytic response following RANKL injection over the calvaria of NLRP12-deficient chimeric mice compared with wild-type control mice. Thus, modulation of NLRP12 levels controls alternative NF-κB signaling in OC precursors, altering bone homeostasis and osteolytic responses.NLRP12 | osteoclast | bone | alternative NF-κB

Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis

“…Moreover, this NLRP12-mediated suppression limits overt TNF-induced inflammation that could lead to HSC apoptosis by limiting canonical NFκB signaling. Our findings add to the studies that suggest that NLRP12 acts as a cellular rheostat to limit inflammation, and is emerging as a “checkpoint” or inhibitor (17, 22) of canonical NFκB signaling (17, 32, 39, 40). Although we demonstrate increased p-IkB and pp65 levels in CD34+ cells from NLRP12 deficient mice undergoing RCI, suggestive of increased canonical NFkB signaling, it does not rule out a role for the non-canonical pathway, which could be evaluated by measuring either NIK or p100 processing.…”

“…Both the canonical and non-canonical pathways of NFκB have been shown to be negatively regulated by NLRP12 (13, 17, 22). We therefore examined NLRP12-dependent activation of key regulators of each pathway.…”

“…Some NLR proteins have been shown to be positive regulators of NF-κB, while NLRP12 has been implicated as a negative regulator of both the canonical and non-canonical pathways of NF-κB (17–21). NLRP12-mediated NF-κB suppression has been implicated in colonic inflammation and tumorigenesis (17) and osteoclast differentiation (22). …”

Inflammatory osteolysis: a conspiracy against bone

“…In addition to the caspase 1-mediated IL-1β processing event, NLRP3 activation induces expression of a variety of cytokines in an NF-κB-dependent, caspase 1-independent fashion (158). As discussed above, although individual inflammasome factors may inhibit osteoclast formation or function, combined release is highly osteolytic (151,159,160).…”

Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma

“…The role of NLRP12 in attenuating these inflammatory disorders was explained by the fact that NLRP12 downregulates NF-κB and ERK activation in T cells [71]. Deficiency of NLRP12 also promotes proliferation of osteocytes, hepatocytes, and microglia [28,76,77]. In the intestine, NLRP12-mediated regulation of inflammatory responses may shape gut microbiota composition [78,79].…”