Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice

Abstract

The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue “spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling.

Inflammatory osteolysis: a conspiracy against bone

“…Inflammasomes are intracellular protein complexes expressed mainly by myeloid cells, including osteoclasts (98,99), but also develop in osteoblasts and chondrocytes (98,100,101). They protect against infections upon recognition of microbial structures known as pathogen-associated molecular patterns (PAMPs) (102).…”

“…While it has yet to be studied in the context of RA, PARP1 proteolysis occurs during osteoclastogenesis (98,99,112,113). A proteolytically stable PARP1 mutant antagonizes osteoclastogenesis, whereas PARP1 deficiency enhances this process (107, 114), indicating that PARP1 negatively regulates osteoclast differentiation.…”

“…IL-1-blocking agents have limited efficacy against NOMID skeletal lesions, while other symptoms related to systemic inflammation are rapidly resolved (119)(120)(121)(122). While the human disease is phenocopied in mouse models with global NOMID mutation (98,123), mice bearing the mutation only in osteoclasts lack systemic inflammation but have severe osteoporosis (99), indicating a cell-autonomous role in the bone-resorptive cell.…”

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

“…Therefore, mouse models are essential to understand the pathogenesis of molecular-genetic disorders of hearing loss. Nlrp3 knockin mouse models of CAPS have been generated (29)(30)(31) but exhibit growth delay, low body weight, and die before 2-3 wk of age. Since this is the age at which wild-type cochleae finally acquire normal auditory structure and function (32), mouse models have not yet provided insight into the pathogenesis of hearing loss caused by NLRP3 mutations.…”

Reprint of: The Great Beauty of the osteoclast

“…Indeed, osteoclasts express several components of the inflammasome cascade (Fig. 7), that are known to lead to caspase-1 activation, pro-IL-1b and pro-IL18 expression, cleavage and release in active forms, typical of the innate immune response [81]. Osteoclasts also express the adenosine triphosphate (ATP) receptor, P2X 7 [82] (Fig.…”