Differential Macrophage Polarization in Male and Female BALB/c Mice Infected With Coxsackievirus B3 Defines Susceptibility to Viral Myocarditis
Differential Macrophage Polarization in Male and Female BALB/c Mice Infected With Coxsackievirus B3 Defines Susceptibility to Viral Myocarditis
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DOI：
10.1161/circresaha.109.195230
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发表时间：
2009-08-14
影响因子：
20.1
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
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作者：
Li, Kang;Xu, Wei;Xiong, Sidong
理由：心肌浸润巨噬细胞在柯萨奇病毒B3（CVB 3）感染的雄性BALB/c小鼠病毒性心肌炎的发病机制中起重要作用。有趣的是，在急性心肌炎期间，在雌性小鼠的心肌中观察到相当的巨噬细胞数量。目的：鉴于CVB 3感染引起雄性小鼠而不是雌性小鼠的严重心肌炎，我们假设浸润雌性小鼠心肌的巨噬细胞可能显示出不同的功能特性，这有助于对CVB 3心肌炎的不同易感性。在这里，我们发现来自CVB 3感染的雄性小鼠的心肌浸润巨噬细胞表达高水平的经典活化巨噬细胞（M1）标志物，包括诱导型一氧化氮合酶、白细胞介素-12、肿瘤坏死因子-α和CD 16/32，而雌性则显示与交替激活的巨噬细胞（M2）表型相关的巨噬细胞甘露糖受体（MMR）和巨噬细胞半乳糖型C型凝集素（MGL）的表达增强。此外，不同的心肌源性细胞因子被发现在CVB 3感染后的性别之间的差异巨噬细胞极化中发挥关键作用。体外程序化M1巨噬细胞的连续转移，如ESTA，显着增加雄性和雌性小鼠的心肌炎。引人注目的是，转移到易感的雄性小鼠M2巨噬细胞显着减轻心肌炎症，通过调节当地的细胞因子谱和促进外周调节性T细胞（Treg）differentiation.Conclusions：两者合计，这项研究可能有助于了解潜在的性别偏见的易感性CVB 3心肌炎和炎症性心脏病的治疗策略的基础上巨噬细胞极化的机制。(Circ Res. 2009; 105：353-364）。
Rational: Myocardial infiltrating macrophages play an important role in the pathogenesis of viral myocarditis in male BALB/c mice following coxsackievirus B3 (CVB3) infection. Interestingly, comparable macrophage numbers were observed in the myocardium of female mice during acute myocarditis.Objective: Given CVB3 infection causes severe myocarditis in male but not female mice, we postulated that macrophages infiltrating the myocardium of female mice may display distinct functional properties that contribute to differential susceptibility to CVB3 myocarditis.Methods and Results: Here, we found that myocardial infiltrating macrophages from CVB3-infected male mice expressed high levels of classically activated macrophages (M1) markers, including inducible nitric oxide synthase, interleukin-12, tumor necrosis factor-alpha, and CD16/32, whereas those of females showed enhanced expression of arginase 1, interleukin-10, macrophage mannose receptor (MMR) and macrophage galactose type C-type lectin (MGL) that were associated with alternatively activated macrophage (M2) phenotype. Moreover, distinct myocardial-derived cytokines were found to play a critical role in differential macrophage polarization between sexes after CVB3 infection. Adoptive transfer of ex vivo programmed M1 macrophages, as expectedly, significantly increased myocarditis in both male and female mice. Strikingly, transfer of M2 macrophages into susceptible male mice remarkably alleviated myocardial inflammation by modulating local cytokine profile and promoting peripheral regulatory T cell (Treg) differentiation.Conclusions: Taken together, this study may facilitate the understanding of the mechanism underlying gender bias in susceptibility to CVB3 myocarditis and the development of therapeutic strategies based on macrophage polarization for inflammatory heart disease. (Circ Res. 2009; 105: 353-364.)