Cutting edge: cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease.
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-gamma 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.
Frisancho-Kiss
Sylvia
S
Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health and School of Medicine, Baltimore, MD 21205, USA.
Davis
Sarah E
SE
Nyland
Jennifer F
JF
Frisancho
J Augusto
JA
Cihakova
Daniela
D
Barrett
Masheka A
MA
Rose
Noel R
NR
Fairweather
Delisa
D
D000818:Animals; D003384:Coxsackievirus Infections / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D029822:Enterovirus B, Human / Q000276:immunology; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D020239:Receptor Cross-Talk / Q000276:immunology*; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D011991:Receptors, Virus; D051197:Toll-Like Receptor 4