NLRP3 inflammasome up-regulates major histocompatibility complex class I expression and promotes inflammatory infiltration in polymyositis

Abstract

Objective This study was designed to investigate the role of the nucleotide-binding-domain -and leucine-rich repeat -containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome in the pathogenesis of polymyositis (PM). Methods Immunochemistry was performed to analyze the NLRP3, caspase-1 and interleukin-1 beta (IL-1β) expression in the muscle tissue of PM patients. Rat model of PM and C2C12 cell were used to investigate the potential role of NLRP3 inflammasome in PM. Results The percentage of CD 68+ macrophages, and the expression levels of NLRP3, caspase-1 and IL-1β in the muscle tissue were elevated in 27 PM patients. LPS/ATP treatment resulted in activation of NLRP3 inflammasome and secretion of IL-1β as well as interferons (IFNs) and monocyte chemotactic protein-1 (MCP-1) in the Raw 264.7 macrophages. Meanwhile, LPS/ATP challenged activation of NLRP3 inflammasome induced overexpression of major histocompatibility complex class I (MHC-I), a key molecular of PM in the co-cultured C2C12 cells. The effect was decreased by treatment of NLRP3 inflammasome inhibitor MCC950 or siRNA of NLRP3 inflammasome. These findings suggested certain levels of IL-1β rather than IFNs up-regulated MHC-I expression in C2C12 cells. IL-1β blockade using neutralizing IL-1β monoclonal antibody or siRNA of IL-1β suppressed MHC-I overexpression. In vivo, NLRP3 inflammasome inhibition by MCC950 reduced the expression of NLRP3, IL-1β and MHC-I in the muscle tissue of PM modal rats. Also, it attenuated the intensity of muscle inflammation as well as the CRP, CK, and LDH levels in the serum. Conclusion NLRP3/caspase-1/IL-1β axis may play an important role in the development of PM. Inhibition of NLRP3 activation may hold promise in the treatment of PM.

Idiopathic inflammatory myopathies: one year in review 2023

“…In particular, macrophages, NLRP3, caspase-1 and IL-1β are hyper-expressed in muscle biopsies from PM patients; consequently, and more importantly, the inhibition of NLRP3 through MCC950 or siRNA leads to an overall attenuation of muscle inflammation, as well as of serum myonecrosis biomarkers (19). Similar evidence has been found for IBM, in which the evidence of the upregulation of the IL-1 axis could potentially pave the way for novel treatments (20).…”

Exercise, mitochondrial dysfunction and inflammasomes in skeletal muscle

“…Mitochondrial dysfunction and aberrant MQC are also known contributors to the pathogenesis of DMD and myositis, characterized by impeded respiration, increases in ROS production, abnormal morphology and impaired mitophagy [ 63 , 64 ]. Increases in mtDAMPs have been observed in pathological muscle, including mitochondrial ROS and damaged mtDNA to increase the expression of NLRP3, ASC, mature caspase-1 and IL-1 [ 65 ] and promoting muscle dysfunction [ 66 , 67 ]. In both pathologies, knockdown or inhibition of NLRP3 reduced the expression of inflammatory markers and rescued impairments in muscle force, endurance capacity and markers of muscle injury [ 50 , 65 ].…”

“…Increases in mtDAMPs have been observed in pathological muscle, including mitochondrial ROS and damaged mtDNA to increase the expression of NLRP3, ASC, mature caspase-1 and IL-1 [ 65 ] and promoting muscle dysfunction [ 66 , 67 ]. In both pathologies, knockdown or inhibition of NLRP3 reduced the expression of inflammatory markers and rescued impairments in muscle force, endurance capacity and markers of muscle injury [ 50 , 65 ]. Furthermore, the inhibition of NLRP3 results in a downregulation of pyroptosis via gasdermin-D which helps alleviate muscle fibrosis, inflammation and oxidative stress in DMD [ 68 ].…”