Female sex hormones regulate the IL-36 family members in the female reproductive tract and impact HSV-2 pathogenesis

• Published in: The Journal of immunology (1950) 2018-05, Vol.200 (1_Supplement), p.126-126.17
• Main Authors: Gardner, Jameson K., Alexander, Thessaly, Herbst-Kralovetz, Melissa M.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.200.Supp.126.17

Recently, the contraceptive Depo-Provera (DMPA) has been linked to an increased risk of sexually transmitted infection acquisition (e.g. HSV-2 and HIV). However, a fundamental gap exists in the understanding of specific mechanisms whereby DMPA use increases risk for HSV-2 infection. IL-36γ is a novel regulator of mucosal inflammation in the female reproductive tract (FRT) and we have shown that IL-36γ is induced in response to HSV-2. One study reported that IL-36γ was the only cytokine upregulated in cervicovaginal secretions from HSV-2 seropositive DMPA users, suggesting that IL-36γ may be a link between DMPA use and HSV-2 infection. We hypothesize that DMPA suppresses IL-36γ expression in the vaginal environment, thereby increasing susceptibility to genital HSV-2 infection. We found that DMPA treatment in mice decreased expression of the IL-36 cytokines in the FRT, while β-estradiol treatment increased expression. To evaluate the impact of IL-36γ on HSV-2 pathogenesis, we used an intravaginal challenge model and treated mice with DMPA to enhance susceptibility to infection. Mice treated with IL-36γ 4h prior to lethal challenge exhibited a delay in disease onset, less severe disease, decreased vaginal viral replication, increased disease resolution and overall survival. IL-36γ treatment increased levels of pro-inflammatory cytokines in vaginal lavages 4h after treatment, and neutrophil recruitment was enhanced and corresponded with increased levels of chemokines. Together, we demonstrate that IL-36γ is hormonally regulated in the FRT and that treatment with IL-36γ promotes the transient induction of immune mediators and neutrophil recruitment in the vaginal microenvironment that result in increased HSV-2 clearance.