Chronic inflammation triggered by the NLRP3 inflammasome in myeloid cells promotes growth plate dysplasia by mesenchymal cells

Abstract

Skeletal complications are common features of neonatal-onset multisystem inflammatory disease (NOMID), a disorder caused by NLRP3-activating mutations. NOMID mice in which NLRP3 is activated globally exhibit several characteristics of the human disease, including systemic inflammation and cartilage dysplasia, but the mechanisms of skeletal manifestations remain unknown. In this study, we find that activation of NLRP3 in myeloid cells, but not mesenchymal cells triggers chronic inflammation, which ultimately, causes growth plate and epiphyseal dysplasia in mice. These responses are IL-1 signaling-dependent, but independent of PARP1, which also functions downstream of NLRP3 and regulates skeletal homeostasis. Mechanistically, inflammation causes severe anemia and hypoxia in the bone environment, yet down-regulates the HIF-1α pathway in chondrocytes, thereby promoting the demise of these cells. Thus, activation of NLRP3 in hematopoietic cells initiates IL-1β-driven paracrine cascades, which promote abnormal growth plate development in NOMID mice.

Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals

“…From among these syndromes, neonatal-onset multisystem inflammatory disease (NOMID) is the most severe phenotype ( Agostini et al, 2004 ; de Jesus et al, 2015 ; Hoffman and Broderick, 2016 ). To determine whether p38α–MK2 regulates inflammasome priming signals, we used NOMID mice expressing constitutively activated NLRP3 in myeloid cells driven by lysozyme M-Cre ( Qu et al, 2015 ; Wang et al, 2017 ). The phenotype of these mice resembles that of mice globally expressing NLRP3 mutant, although the disease is less severe in mice with myeloid-restricted expression of the transgene ( Bonar et al, 2012 ; Qu et al, 2015 ; Wang et al, 2017 ).…”

PARP1 Hinders Histone H2B Occupancy at the NFATc1 Promoter to Restrain Osteoclast Differentiation

“…PARP1 D214N inhibited OC differentiation driven by hyperactivated NLRP3 inflammasome, although it did not affect inflammatory responses such as leukocytosis and splenomegaly caused by this inflammasome, as we previously reported . Conversely, mice lacking PARP1 globally or in myeloid cells exhibited a low bone mass phenotype marked by increased OC differentiation.…”

Omnipresence of inflammasome activities in inflammatory bone diseases

“…Systemic inflammation and multiple organ pathologies, including bone abnormalities, are entirely prevented in NOMID mice lacking IL-1 receptor [75]. However, persistent residual inflammation is reported in FCAS mice and MWS mice deficient in IL-1 and IL-18 signaling [78,79].…”

“…Unexpectedly, conditional activation of NLRP3 in myeloid cells but not in osteochondro-progenitors reproduces the abnormal cartilage features, suggesting that the phenotype is not chondrocyte autonomous [75]. CAPS mice also exhibit severe low bone mass, a phenotype that correlates with a massive expansion of osteoclast precursors, exuberant osteoclastogenesis, and increased osteoclast activity [41,73,[75][76][77]. Thus, while the magnitude of bone resorption in CAPS patients is not known, this process is prominent and well characterized in mouse models.…”

“…NOMID mice in which NLRP3 is activated globally exhibit normal patterning of skeletal elements but display hypocellular epiphyses due to massive chondrocyte death, and disorganized growth plate matrix protruding towards the bone marrow cavity [73]. Unexpectedly, conditional activation of NLRP3 in myeloid cells but not in osteochondro-progenitors reproduces the abnormal cartilage features, suggesting that the phenotype is not chondrocyte autonomous [75]. CAPS mice also exhibit severe low bone mass, a phenotype that correlates with a massive expansion of osteoclast precursors, exuberant osteoclastogenesis, and increased osteoclast activity [41,73,[75][76][77].…”