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

被引：60

作者：

Kobayashi, Motoi ^{[1
]}

Usui, Fumitake ^{[1
]}

Karasawa, Tadayoshi ^{[1
]}

Kawashima, Akira ^{[1
]}

Kimura, Hiroaki ^{[1
]}

Mizushina, Yoshiko ^{[1
]}

Shirasuna, Koumei ^{[1
]}

Mizukami, Hiroaki ^{[2
]}

Kasahara, Tadashi ^{[1
]}

Hasebe, Naoyuki ^{[3
]}

Takahashi, Masafumi ^{[1
]}

机构：

[1] Jichi Med Univ, Ctr Mol Med, Div Inflammat Res, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan

[2] Jichi Med Univ, Div Genet Therapeut, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan

[3] Asahikawa Med Univ, Div Cardiovasc Resp & Neurol, Dept Med, 2-1-1-1 Midorigaoka Higashi, Asahikawa, Hokkaido, Japan

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

日本学术振兴会;

关键词：

BRUTONS TYROSINE KINASE; INFLAMMASOME ACTIVATION; INDUCED CARDIOMYOPATHY; CARDIAC DYSFUNCTION; MICE DEFICIENT; INJURY; ATHEROSCLEROSIS; CONTRIBUTES; INHIBITION; MECHANISMS;

D O I：

10.1038/srep26489

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

NLRP3 inflammasomes recognize non-microbial danger signals and induce release of proinflammatory cytokine interleukin (IL)-1 beta, 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-1 beta(-/-) mice, indicating that NLRP3 deficiency enhanced the susceptibility to Dox-induced cardiotoxicity independent of IL-1 beta. 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-1 beta. Our findings identify a novel role of NLRP3 and provided new insights into the mechanisms underlying Dox-induced cardiotoxicity.

引用

页数：11

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