Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice

Abstract

Mutated NLRP3 assembles a hyperactive inflammasome, which causes excessive secretion of interleukin (IL)-1β and IL-18 and, ultimately, a spectrum of autoinflammatory disorders known as cryopyrinopathies of which neonatal-onset multisystem inflammatory disease (NOMID) is the most severe phenotype. NOMID mice phenocopy several features of the human disease as they develop severe systemic inflammation driven by IL-1β and IL-18 overproduction associated with damage to multiple organs, including spleen, skin, liver, and skeleton. Secretion of IL-1β and IL-18 requires gasdermin D (GSDMD), which—upon activation by the inflammasomes—translocates to the plasma membrane where it forms pores through which these cytokines are released. However, excessive pore formation resulting from sustained activation of GSDMD compromises membrane integrity and ultimately causes a pro-inflammatory form of cell death, termed pyroptosis. In this study, we first established a strong correlation between NLRP3 inflammasome activation and GSDMD processing and pyroptosis in vitro. Next, we used NOMID mice to determine the extent to which GSDMD-driven pyroptosis influences the pathogenesis of this disorder. Remarkably, all NOMID-associated inflammatory symptoms are prevented upon ablation of GSDMD. Thus, GSDMD-dependent actions are required for the pathogenesis of NOMID in mice.

Inflammasomes in neuroinflammatory and neurodegenerative diseases

“…Similarly, GSDMD was shown to control inflammasome‐driven pathology in neonatal‐onset multisystem inflammatory disease (NOMID), which is caused by activating mutations in the inflammasome sensor NLRP3 (Xiao et al , ). Indeed, FMF knockin mice and NOMID mice were shown to be fully protected from developing the respective autoinflammatory syndromes when crossed into a Gsdmd‐deficient background (Kanneganti et al , ; Xiao et al , ). GSDMD was also demonstrated to play a key role in the pathogenesis of steatohepatitis by controlling cytokine secretion, and Gsdmd knockout mice exhibit decreased severity of steatosis and inflammation in a high‐fat diet‐induced model of non‐alcoholic steatohepatitis (Xu et al , ).…”

“…Hence, GSDMD inhibition has been proposed as a novel therapeutic strategy to prevent inflammasome-driven pathology in different diseases. Pyroptosis has recently been shown to be the critical mechanism of IL-1bmediated systemic pathology in the autoinflammatory disease Familial Mediterranean Fever (FMF), which is caused by missense mutations in Mefv that activates the pyrin inflammasome (Kanneganti et al, 2018). Similarly, GSDMD was shown to control inflammasome-driven pathology in neonatal-onset multisystem inflammatory disease (NOMID), which is caused by activating mutations in the inflammasome sensor NLRP3 (Xiao et al, 2018).…”

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…In mouse models of CAPS and FMF, IL-1β production, neutrophilia, and tissue damage are dependent on GSDMD, suggesting that pyroptosis is a critical mechanism of inflammatory pathology in autoinflammatory diseases. 120,121 Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis, an inflammatory demyelinating disease mediated by Th1 and Th17 cells that react with myelin antigens. In EAE, GSDMD expressed in peripheral myeloid cells is required for the development of pathogenic Th1/Th17 cells, neuroinflammation, and disease progression.…”

Inflammasomes in the pathophysiology of autoinflammatory syndromes

“…[38][39][40] Results of several studies in mouse models suggest that inflammasome function increases in CAPS, with an increase in caspase-1 activity, release of IL-1 , and various forms of cell death observed. [41][42][43] Remarkably, all NOMID-associated inflammatory symptoms are prevented upon ablation of GSDMD, 44 suggesting that GSDMD-dependent actions are required for the pathogenesis of NOMID in mice.…”