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

Sheri L Bonar,Soumya Ravindran,James L Mueller,Hal M Hoffman,Cynthia L Hickman-Brecks,Gabriel Mbalaviele,Matthew D Mcgeough,Daniel L Kastner,Deborah V Novack,Susan K Grimston,Susannah D Brydges,Roberto Civitelli,Audrey Mcalinden,Carla Pena,Debbie Chen

doi:10.1371/journal.pone.0035979

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.

Highlights

NLRP3, called cryopyrin, is one of the most studied members of the NOD-like receptor (NLR) family, which are intracellular proteins involved in the initiation of the innate immune response
80 pathogenic mutations in the NLRP3 gene have been identified in patients with systemic autoinflammatory disorders known as cryopyrinopathies or cryopyrin-associated periodic syndromes (CAPS), which include neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS) [8]
Zona pelucida 3-Cre was used to induce global expression of D301N NLRP3 similar to that observed in NOMID patients

Summary

Introduction

NLRP3, called cryopyrin, is one of the most studied members of the NOD-like receptor (NLR) family, which are intracellular proteins involved in the initiation of the innate immune response. The NLRP3 inflammasome is activated by multiple danger-associated moieties, including ATP, glucose, monosodium urate, calcium pyrophosphate dihydrate and cholesterol crystals [3,4,5]. Dysregulated activation of this inflammasome is believed to be involved in the pathogenesis of various inflammatory and metabolic diseases such as gout, pseudogout, type-2 diabetes and atherosclerosis [3,5,6,7]. 80 pathogenic mutations in the NLRP3 gene have been identified in patients with systemic autoinflammatory disorders known as cryopyrinopathies or cryopyrin-associated periodic syndromes (CAPS), which include neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS) [8]. Abnormal endochondral ossification was suspected in these patients [12]

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Conclusion