Differential macrophage polarization in male and female BALB/c mice infected with coxsackievirus B3 defines susceptibility to viral myocarditis.
BACKGROUND
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.


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.
Li
Kang
K
Institute for Immunobiology, Department of Immunology, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China.
Xu
Wei
W
Guo
Qiang
Q
Jiang
Zhenggang
Z
Wang
Ping
P
Yue
Yan
Y
Xiong
Sidong
S
D019264:Adoptive Transfer; D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D003384:Coxsackievirus Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D016207:Cytokines / Q000096:biosynthesis; D004198:Disease Susceptibility / Q000378:metabolism / Q000473:pathology / Q000821:virology; D029822:Enterovirus B, Human; D005260:Female; D037181:Lectins, C-Type / Q000096:biosynthesis; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation / Q000821:virology; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D017452:Receptors, IgG / Q000096:biosynthesis; D012727:Sex Characteristics
D016207:Cytokines; C499172:Fcgr2b protein, mouse; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase