NLRP3 inflammasome-driven IL-1β and IL-18 contribute to lipopolysaccharide-induced septic cardiomyopathy

• Published in: Journal of molecular and cellular cardiology Vol. 180; pp. 58 - 68
• Main Authors: Fujimura, Kenta, Karasawa, Tadayoshi, Komada, Takanori, Yamada, Naoya, Mizushina, Yoshiko, Baatarjav, Chintogtokh, Matsumura, Takayoshi, Otsu, Kinya, Takeda, Norihiko, Mizukami, Hiroaki, Kario, Kazuomi, Takahashi, Masafumi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2023
• Subjects: Animals; Cardiomyopathies - genetics; Cardiomyopathy; Caspase 1 - genetics; Caspase 1 - metabolism; Cytokine, heart; Cytokines; Inflammasomes - metabolism; Inflammation; Interleukin; Interleukin-18 - genetics; Interleukin-1beta - metabolism; Lipopolysaccharides - adverse effects; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Inflammation; Cardiomyopathy; Cytokine, heart; Interleukin
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2023.05.003

Sepsis is a life-threatening syndrome, and its associated mortality is increased when cardiac dysfunction and damage (septic cardiomyopathy [SCM]) occur. Although inflammation is involved in the pathophysiology of SCM, the mechanism of how inflammation induces SCM in vivo has remained obscure. NLRP3 inflammasome is a critical component of the innate immune system that activates caspase-1 (Casp1) and causes the maturation of IL-1β and IL-18 as well as the processing of gasdermin D (GSDMD). Here, we investigated the role of the NLRP3 inflammasome in a murine model of lipopolysaccharide (LPS)-induced SCM. LPS injection induced cardiac dysfunction, damage, and lethality, which was significantly prevented in NLRP3−/− mice, compared to wild-type (WT) mice. LPS injection upregulated mRNA levels of inflammatory cytokines (Il6, Tnfa, and Ifng) in the heart, liver, and spleen of WT mice, and this upregulation was prevented in NLRP3−/− mice. LPS injection increased plasma levels of inflammatory cytokines (IL-1β, IL-18, and TNF-α) in WT mice, and this increase was markedly inhibited in NLRP3−/− mice. LPS-induced SCM was also prevented in Casp1/11−/− mice, but not in Casp11mt, IL-1β−/−, IL-1α−/−, or GSDMD−/− mice. Notably, LPS-induced SCM was apparently prevented in IL-1β−/− mice transduced with adeno-associated virus vector expressing IL-18 binding protein (IL-18BP). Furthermore, splenectomy, irradiation, or macrophage depletion alleviated LPS-induced SCM. Our findings demonstrate that the cross-regulation of NLRP3 inflammasome-driven IL-1β and IL-18 contributes to the pathophysiology of SCM and provide new insights into the mechanism underlying the pathogenesis of SCM. [Display omitted] •NLRP3 inflammasome is required for the development of LPS-induced SCM.•IL-1β deficiency with AAV-mediated overexpression of IL-18BP prevented the development of LPS-induced SCM although deficiency of IL-1β, GSDMD, or IL-1α alone failed to prevent it.•Splenectomy, irradiation, or macrophage depletion alleviated LPS-induced SCM and the production of IL-1β and IL-18.