A TNF family receptor regulates epithelial innate responses and host defense against pathogenic bacterial infections of the mucosa (49.1)

Abstract

Abstract Previously, in a mouse colitis model, we demonstrated an anti-inflammatory role for the herpes virus entry mediator (HVEM), a TNF superfamily receptor, when expressed by a radiation resistant cell population (J. Exp. Med. 205: 1463, 2008). However, the molecular mechanism for HVEM function remained to be determined. We therefore explored the role of HVEM in colonic epithelial cells, a radiation resistant cell type critical for preventing colitis and enhancing host defense. During Citrobacter rodentium infection, Hvem-/- mice had impaired colonic epithelial responses, resulting in higher bacterial burdens, inflammation and increased mortality. HVEM stimulation induced epithelial responses by NIK-dependent Stat3 activation, resulting in the expression of genes important for mucosal immunity. HVEM signaling also induced IL-22R1 expression, which boosted IL-22 signaling, leading to enhanced Stat3 activation in the epithelium. While HVEM or IL-22R signaling alone induced Stat3 activation in epithelial cells in vitro, during infection in vivo, both Stat3-activating pathways were required. Likewise, in Streptococcus pneumoniae infection, HVEM was required not only for survival and bacterial clearance, but also for Stat3 activation and induction of innate responses in the lung. Collectively, our findings establish HVEM as a crucial regulator of innate defense at mucosal surfaces via directly enhancing epithelial Stat3 activation and by inducing epithelial IL-22R1 expression.