Sex differences in coxsackievirus B3-induced myocarditis: IL-12Rβ1 signaling and IFN-γ increase inflammation in males independent from STAT4

Frisancho-Kiss, Sylvia; Nyland, Jennifer E.; Davis, Sarah E.; Frisancho, J. Augusto; Barrett, Masheka A.; Rose, Noel R.; Fairweather, De Lisa

doi:10.1016/j.brainres.2006.08.003

Cited by 77 publications

(86 citation statements)

References 42 publications

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“…1A), which was confirmed by FACS analysis of CD45 ϩ immune cells (Fig. 1B) (8). Males had significantly increased numbers of monocyte/macrophages, granulocytes, MC, and dendritic cells (DC), whereas females had significantly increased numbers of B cells in the heart (Fig.…”

Section: Increased Inflammation In Males Not Due To Virussupporting

confidence: 54%

“…1D) or day 12 p.i. (females 229 Ϯ 137 vs males 657 Ϯ 329 PFU/g heart), indicating that factors other than viral replication increase inflammation in males (8,13). We found previously that increased IL-1␤ and IL-18 levels correlate with more severe myocarditis in male BALB/c mice (10,13).…”

Section: Increased Inflammation In Males Not Due To Virusmentioning

confidence: 67%

“…We found that TLR4 levels were not decreased on APC in IFN-␥-deficient males (data not shown), indicating that IFN-␥ does not increase TLR4 expression in males. These data suggest that elevated TLR4 expression in males leads to a Th1 response via increased IL-18 (IFN-␥-inducing factor) (8,10).…”

Section: Males and Females Express Different Levels Of Tlr4 And Tim-3mentioning

confidence: 82%

“…Previously, we reported that gonadectomy of male mice reduces myocarditis, indicating that testosterone increases inflammation in the heart (7). In contrast, STAT4-induced IFN-␥ was not found to increase inflammation in males (8). In this study, we further examine mechanisms that increase inflammation in the heart of male mice.…”

mentioning

confidence: 86%

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Cutting Edge: Cross-Regulation by TLR4 and T cell Ig Mucin-3 Determines Sex Differences in Inflammatory Heart Disease

Frisancho-Kiss

Davis

Nyland

et al. 2007

The Journal of Immunology

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188

271

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Recent clinical studies have reinforced the importance of sex-related differences in the pathogenesis of cardiovascular diseases, with an increased incidence and mortality in men. Similar to humans, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe inflammation in the heart even though viral replication is no greater than in females. We show that TLR4 and IFN-γ levels are significantly elevated and regulatory T cell (Treg) populations significantly reduced in the heart of males following CVB3 infection, whereas females have significantly increased T cell Ig mucin (Tim)-3, IL-4 and Treg. Blocking Tim-3 in males significantly increases inflammation and TLR4 expression while reducing Treg. In contrast, defective TLR4 signaling significantly reduces inflammation while increasing Tim-3 expression. Cross-regulation of TLR4 and Tim-3 occurs during the innate and adaptive immune response. This novel mechanism may help explain why inflammatory heart disease is more severe in males.

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Section: Increased Inflammation In Males Not Due To Virussupporting

confidence: 54%

Section: Increased Inflammation In Males Not Due To Virusmentioning

confidence: 67%

Section: Males and Females Express Different Levels Of Tlr4 And Tim-3mentioning

confidence: 82%

mentioning

confidence: 86%

See 2 more Smart Citations

Cutting Edge: Cross-Regulation by TLR4 and T cell Ig Mucin-3 Determines Sex Differences in Inflammatory Heart Disease

Frisancho-Kiss

Davis

Nyland

et al. 2007

The Journal of Immunology

Self Cite

188

271

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“…6 However, this view does not apply to myocarditis because male mice develop more severe viral-induced myocarditis 7,8 and are often used exclusively in studies involving autoimmune-mediated myocarditis. 9,10 In this context, we chose to investigate the immunological features surrounding the male-biased incidence seen in human DCM 11 using our recently-developed murine model of experimental autoimmune myocarditis (EAM).…”

Section: 2 This View Is Supported By Studies Correlating Increased mentioning

confidence: 99%

Sex-Defined T-Cell Responses to Cardiac Self Determine Differential Outcomes of Murine Dilated Cardiomyopathy

Jane‐wit

Altuntas

Monti

et al. 2008

The American Journal of Pathology

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Idiopathic dilated cardiomyopathy (DCM) is a disease of putative autoimmune origin that kills males at a twofold to threefold greater frequency than females. The reasons underlying these differential outcomes may be related to sex-divergent self-recognition. Here we examined sex-specific autoimmune responses to cardiac self and their impact on DCM development. We found that males immunized to the p406-425 peptide derived from mouse cardiac ␣-myosin heavy chain preferentially develop a predominant Th17 lineage response that provides sustained T-cell memory and a high DCM incidence whereas females preferentially develop a predominant Th1 lineage response that becomes anergized to cardiac self resulting in compensatory protection against DCM. The distinct sex-defined disease phenotypes are interchangeable after in vivo manipulation of Th1 (interleukin-2) and Th17 (interleukin-17) cytokines. Our study shows that male and female SWXJ mice differentially respond to cardiac self in ways that lead to distinct autoimmune outcomes and implies that optimized therapy for autoimmunity may require consideration of the qualitatively different ways that males and females engage self.

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An overview of the immune mechanisms of viral myocarditis

Lasrado

Reddy

2020

Reviews in Medical Virology

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Viral myocarditis has been identified as a major cause of dilated cardiomyopathy (DCM) that can lead to heart failure. Historically, Coxsackieviruses and adenoviruses have been commonly suspected in myocarditis/DCM patients in North America and Europe. However, this notion is changing as other viruses such as Parvovirus B19 and human herpesvirus-6 are increasingly reported as causes of myocarditis in the United States, with the most recent example being the severe acute respiratory syndrome coronavirus 2, causing the Coronavirus Disease-19. The mouse model of Coxsackievirus B3 (CVB3)-induced myocarditis, which may involve mediation of autoimmunity, is routinely used in the study of immune pathogenesis of viral infections as triggers of DCM. In this review, we discuss the immune mechanisms underlying the development of viral myocarditis with an emphasis on autoimmunity in the development of post-infectious myocarditis induced with CVB3.

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Sex differences in coxsackievirus B3-induced myocarditis: IL-12Rβ1 signaling and IFN-γ increase inflammation in males independent from STAT4

Cited by 77 publications

References 42 publications

Cutting Edge: Cross-Regulation by TLR4 and T cell Ig Mucin-3 Determines Sex Differences in Inflammatory Heart Disease

Cutting Edge: Cross-Regulation by TLR4 and T cell Ig Mucin-3 Determines Sex Differences in Inflammatory Heart Disease

Sex-Defined T-Cell Responses to Cardiac Self Determine Differential Outcomes of Murine Dilated Cardiomyopathy

An overview of the immune mechanisms of viral myocarditis

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