title: NLRP3 Deficiency Reduces Macrophage Interleukin-10 Production and Enhances the Susceptibility to Doxorubicin-induced Cardiotoxicity.
abstract: 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.
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Fumitake
authors.initials: F
authors.lastname: Usui
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Karasawa
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawashima
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mizushina
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Koumei
authors.initials: K
authors.lastname: Shirasuna
authors.affiliation: Division of Genetic Therapeutics, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
authors.affiliation: Department of Medicine, Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa, Hokkaido, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hasebe
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D066126:Cardiotoxicity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D006335:Heart Injuries / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000172:deficiency / Q000235:genetics*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000172:deficiency / Q000235:genetics*
chemical_list: C556062:IL10 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016753:Interleukin-10; D004317:Doxorubicin