NLRP3 Deficiency Reduces Macrophage Interleukin-10 Production and Enhances the Susceptibility to Doxorubicin-induced Cardiotoxicity

• Published in: Scientific reports 2016-05, Vol.6 (1), p.26489, Article 26489
• Main Authors: Kobayashi, Motoi, Usui, Fumitake, Karasawa, Tadayoshi, Kawashima, Akira, Kimura, Hiroaki, Mizushina, Yoshiko, Shirasuna, Koumei, Mizukami, Hiroaki, Kasahara, Tadashi, Hasebe, Naoyuki, Takahashi, Masafumi
• Format: Article
• Language: English
• Subjects: 13; 13/21; 13/51; 42; 42/44; 631/443/592/75/230; 64/60; Animals; Bone marrow; Bone marrow transplantation; Bone Marrow Transplantation - adverse effects; Cardiotoxicity; Cardiovascular diseases; Cells, Cultured; Cytokines; Disease Models, Animal; Doxorubicin; Doxorubicin - toxicity; Heart diseases; Heart Injuries - chemically induced; Heart Injuries - genetics; Heart Injuries - immunology; Humanities and Social Sciences; Humans; Inflammasomes; Inflammation; Interleukin 10; Interleukin-10 - metabolism; Interleukin-1beta - deficiency; Interleukin-1beta - genetics; Macrophages; Macrophages - immunology; Mice; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein - deficiency; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; Rodents; Science; Science (multidisciplinary); Transplantation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep26489

NLRP3 inflammasomes recognize non-microbial danger signals and induce release of proinflammatory cytokine interleukin (IL)-1β, leading to sterile inflammation in cardiovascular disease. Because sterile inflammation is involved in doxorubicin (Dox)-induced cardiotoxicity, we investigated the role of NLRP3 inflammasomes in Dox-induced cardiotoxicity. Cardiac dysfunction and injury were induced by low-dose Dox (15 mg/kg) administration in NLRP3-deficient (NLRP3 −/− ) mice but not in wild-type (WT) and IL-1β −/− mice, indicating that NLRP3 deficiency enhanced the susceptibility to Dox-induced cardiotoxicity independent of IL-1β. Although the hearts of WT and NLRP3 −/− mice showed no significant difference in inflammatory cell infiltration, macrophages were the predominant inflammatory cells in the hearts, and cardiac IL-10 production was decreased in Dox-treated NLRP3 −/− mice. Bone marrow transplantation experiments showed that bone marrow-derived cells contributed to the exacerbation of Dox-induced cardiotoxicity in NLRP3 −/− mice. In vitro experiments revealed that NLRP3 deficiency decreased IL-10 production in macrophages. Furthermore, adeno-associated virus-mediated IL-10 overexpression restored the exacerbation of cardiotoxicity in the NLRP3 −/− mice. These results demonstrated that NLRP3 regulates macrophage IL-10 production and contributes to the pathophysiology of Dox-induced cardiotoxicity, which is independent of IL-1β. Our findings identify a novel role of NLRP3 and provided new insights into the mechanisms underlying Dox-induced cardiotoxicity.