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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-05-26

AUTHORS

Motoi Kobayashi, Fumitake Usui, Tadayoshi Karasawa, Akira Kawashima, Hiroaki Kimura, Yoshiko Mizushina, Koumei Shirasuna, Hiroaki Mizukami, Tadashi Kasahara, Naoyuki Hasebe, Masafumi Takahashi

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. More... »

PAGES

26489

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/srep26489

DOI

http://dx.doi.org/10.1038/srep26489

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27225830


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55 doxorubicin
56 dysfunction
57 exacerbation
58 experiments
59 findings
60 heart
61 hearts of WT
62 independent
63 infiltration
64 inflammasome
65 inflammation
66 inflammatory cell infiltration
67 inflammatory cells
68 injury
69 insights
70 interleukin
71 interleukin-10 production
72 macrophage IL-10 production
73 macrophages
74 marrow-derived cells
75 mechanism
76 mice
77 new insights
78 novel role
79 overexpression
80 pathophysiology
81 predominant inflammatory cells
82 production
83 proinflammatory cytokines interleukin
84 release
85 results
86 role
87 signals
88 significant differences
89 sterile inflammation
90 susceptibility
91 transplantation experiments
92 wt
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