Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction
Shanshan Cai, Mingyue Zhao, Bo Zhou, Akira Yoshii, Darrian Bugg, Outi Villet, Anita Sahu, Gregory S. Olson, Jennifer Davis, Rong Tian
Shanshan Cai, Mingyue Zhao, Bo Zhou, Akira Yoshii, Darrian Bugg, Outi Villet, Anita Sahu, Gregory S. Olson, Jennifer Davis, Rong Tian
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Research Article Cardiology Metabolism

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction

Abstract

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3–7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions.

Authors

Shanshan Cai, Mingyue Zhao, Bo Zhou, Akira Yoshii, Darrian Bugg, Outi Villet, Anita Sahu, Gregory S. Olson, Jennifer Davis, Rong Tian

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Figure 3

Heightened inflammation is coupled with increased macrophage death and failed transition to a reparative phenotype in mKO mice after MI.

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Heightened inflammation is coupled with increased macrophage death and f...
(A and B) Flow cytometric quantification of neutrophils in blood (A) and infarcted tissue (B) at days 1, 3, and 7 (D1, D3, D7) after mMI (n = 3–8/group). (C–E) Cytokine/chemokine levels of TNF-α, CXCL1, CXCL2, and CCL2 in plasma on day 1 after mMI (C), as well as levels of CXCL1 (D) and CXCL2 (E) chemokines in infarcted tissue at post-MI days 1, 3, and 7 were detected by ELISA (n = 4–6/group). (F–I) Flow cytometric quantification of monocytes (CD45+CD11b+ly6G–) in blood (F) and monocytes and macrophages in infarcted tissue (G) at post-mMI days 1, 3, and 7. Ly6Chi monocytes (H) and CD206+ macrophages (I) in infarcted tissue at post-MI days 1, 3, and 7 (n = 3–10/group). (J) IL-6 cytokine levels in infarcted tissue at post-MI days 1, 3, and 7 were detected by ELISA (n = 3–4/group). (K–L) mRNA levels of selected genes involved in inflammatory responses in cM cells isolated from infarcted tissue at day 3 after MI. RNA was extracted from cM cells and then subjected to quantitative PCR (qPCR) (n = 4/group). Data are presented as the mean ± SEM. (M–Q) Detection of apoptotic neutrophils and macrophages in mouse heart at post-MI day 3. (M) Frozen sections of heart tissue from LysMcre and mKO mice were double stained for Ly6G (green) and Tunel (red), and nuclei were stained with Hoechst (blue) Scale bars: 25 μm. (N) Same sections as in M, stained for CD68 (green) and Tunel (red); nuclei were stained with Hoechst (blue) Scale bars: 50 μm. (O) Quantitative analysis of ly6G+ (green) and ly6G+Tunel+ cells per field (left y axis) and percentage of ly6G+Tunel+ cells per Ly6G+ nuclei in the infarcted area (right y axis). (P) Quantitative analysis of CD68+, CD68+Tunel+ cells per field (left y axis) and percentage of CD68+Tunel+ per CD68+ nuclei in the infarcted area (right y axis) (n = 4/group). Data are presented as the mean ± SEM. (Q) mRNA levels of selected genes involved in apoptotic cell death in cM cells isolated from infarct tissue at post-MI day 3 (n = 4/group). *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test.