Differential Macrophage Polarization in Male and Female BALB/c Mice Infected With Coxsackievirus B3 Defines Susceptibility to Viral Myocarditis

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. OBJECTI...

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Published in:Circulation research 2009-08, Vol.105 (4), p.353-364
Main Authors: Li, Kang, Xu, Wei, Guo, Qiang, Jiang, Zhenggang, Wang, Ping, Yue, Yan, Xiong, Sidong
Format: Article
Language:English
Subjects:
Adoptive Transfer
Animals
Arginase - biosynthesis
Biological and medical sciences
Cardiology. Vascular system
Coxsackievirus Infections - metabolism
Coxsackievirus Infections - pathology
Coxsackievirus Infections - virology
Cytokines - biosynthesis
Disease Susceptibility - metabolism
Disease Susceptibility - pathology
Disease Susceptibility - virology
Enterovirus B, Human
Female
Fundamental and applied biological sciences. Psychology
Heart
Lectins, C-Type - biosynthesis
Macrophage Activation
Macrophages - metabolism
Macrophages - pathology
Macrophages - transplantation
Macrophages - virology
Male
Mannose-Binding Lectins - biosynthesis
Medical sciences
Mice
Mice, Inbred BALB C
Myocarditis - metabolism
Myocarditis - pathology
Myocarditis - virology
Myocarditis. Cardiomyopathies
Myocardium - metabolism
Myocardium - pathology
Nitric Oxide Synthase Type II - biosynthesis
Receptors, Cell Surface - biosynthesis
Receptors, IgG - biosynthesis
Sex Characteristics
Vertebrates: cardiovascular system
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Summary: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-α, 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.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.109.195230