IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Abstract

Herpes simplex virus 2 (HSV-2) causes a persistent, lifelong infection that increases risk for sexually transmitted infection acquisition. Both the lack of a vaccine and the need for chronic suppressive therapies to control infection presents the need to further understand immune mechanisms in response to acute HSV-2 infection. The IL-36 cytokines are recently identified members of the IL-1 family and function as inflammatory mediators at epithelial sites. Here, we first used a well-characterized three-dimensional (3-D) human vaginal epithelial cell (VEC) model to understand the role of IL-36γ in the context of HSV-2 infection. In 3-D VEC, IL-36γ is induced by HSV-2 infection, and pretreatment with exogenous IL-36γ significantly reduced HSV-2 replication. To assess the impact of IL-36γ treatment on HSV-2 disease pathogenesis, we employed a lethal genital infection model. We showed that IL-36γ treatment in mice prior to lethal intravaginal challenge significantly limited vaginal viral replication, delayed disease onset, decreased disease severity, and significantly increased survival. We demonstrated that IL-36γ treatment transiently induced pro-inflammatory cytokines, chemokines, and antimicrobial peptides in murine lower female reproductive tract (FRT) tissue and vaginal lavages. Induction of the chemokines CCL20 and KC in IL-36γ treated mice also corresponded with increased polymorphonuclear (PMN) leukocyte infiltration observed in vaginal smears. Altogether, these studies demonstrate that IL-36γ drives the transient production of immune mediators and promotes PMN recruitment in the vaginal microenvironment that increases resistance to HSV-2 infection and disease. Our data indicate that IL-36γ may participate as a key player in host defense mechanisms against invading pathogens in the FRT.

IL-36γ Is a Key Regulator of Neutrophil Infiltration in the Vaginal Microenvironment and Limits Neuroinvasion in Genital HSV-2 Infection

“…We have demonstrated that IL-36g is expressed in the female reproductive tract (FRT) and is induced in response to an array of microbial products, suggesting a role in host defense mechanisms (19). Indeed, we found that HSV-2 stimulated IL36G expression and that treatment with IL-36g induced an antiviral state that limited viral replication in a human three-dimensional cell culture model and protected against disease pathogenesis after lethal challenge in mice (20). We further revealed that IL-36g transiently induced polymorphonuclear cell recruitment in the FRT that corresponded with decreased vaginal viral titers and increased survival (20).…”

Association between interleukin‑36γ and tumor progression in non‑small cell lung cancer

“…Therefore, the present study aimed to determine whether IL-36 had a similar effect. As a subtype of IL-36, IL-36γ functions in a variety of skin inflammatory reactions and immunopathological processes, such as psoriasis, inflammatory megacolon and infectious diseases (16,(27)(28)(29)(30)(31). Previous studies have demonstrated the involvement of IL-36γ in the differentiation of Th cells and type-1 immune responses (7,16,17).…”

Interleukin-36 family as a novel regulator of inflammation in the barrier tissues

“…В кератиноцитах человека стимуляция in vitro вирусом простого герпеса (HSV-1) приводила к индукции IL-36α, но не индукции IL-36β и IL-36γ [48]. Напротив, повышенные уровни IL-36γ были обнаружены в вагинальных эпителиальных клетках после инфекции HSV-2 [36]. Было обнаружено, что экзогенный IL-36γ способен ингибировать вирусную репликацию.…”

“…Было обнаружено, что экзогенный IL-36γ способен ингибировать вирусную репликацию. Обработка IL-36γ приводила к выработке провоспалительных цитокинов, антимикробных пептидов и хемокинов (например, CCL20) [36].…”

“…Серьезную проблему на сегодняшний день представляет такая патология кожи, как атопический дерматит. Было показано увеличение экспрессии IL-36α, IL-36γ и IL-36ra в пораженной коже пациентов по сравнению с неповрежден- [36,45,48,53,74]. Более того, показано, что эпидермальный фактор роста (EGF) участвует в регуляции IL-36α и IL-36β в коже [32], транскрипционный фактор T-bet регулирует IL-36γ в миелоидных клетках [6].…”