IFN-I exacerbates the inflammatory response of epithelial cells to Chlamydia trachomatis infection by enhancing TLR3 expression.

The inflammation induced by Chlamydia trachomatis infection in the female genital tract can have severe consequences. Recent observations in women and mice infected with Chlamydia suggest that type I interferon (IFN-I) may have deleterious effects. This study aimed to elucidate the consequences of IFN-I production on C. trachomatis-induced inflammation in epithelial cells and the molecular pathway(s) involved. We showed that the combination of IFN-I and Chlamydia resulted in a stronger induction of inflammation than Chlamydia alone, while IFN-I alone had no effect. Inhibiting AKT and mTOR, but not silencing STAT1, significantly attenuated the synergistic effect between IFN-I and bacteria on inflammation. Inhibition of ERK also blocked this synergistic effect, although ERK was not activated by IFN-I. We hypothesized that IFN-I enhanced the expression of a pathogen recognition receptor of the host, thereby potentiating detection of the bacteria and the subsequent inflammatory response. IFN-I, but not C. trachomatis infection, increased the expression of Toll-like receptor 3 (TLR3), and silencing or knocking-out TLR3 prevented the synergistic effect between infection and IFN-I. Furthermore, our data support the presence of dsRNA in infected cells and the activation of the MAPK/ERK and AP-1/ATF2 signaling cascades downstream of TLR3. Taken together, our data demonstrate that IFN-I exacerbates the host inflammatory response triggered by Chlamydia by increasing TLR3 expression and activation, leading to hyperinflammation. The identified signaling cascades represent potential targets for therapeutic intervention to limit tissue damage upon Chlamydia infection.IMPORTANCEThe effect of the production of IFN-I upon infection by Chlamydia trachomatis is not well understood. We showed that IFN-I exacerbated Chlamydia-induced inflammation in epithelial cells. This synergy was mediated by the IFN-induced upregulation of Toll-like receptor 3 (TLR3) expression, which facilitated sensing of Chlamydia and amplified the inflammatory response. We identified the signaling cascades involved upstream and downstream of TLR3 signaling. By exacerbating the pro-inflammatory response of epithelial cells, IFN-I might contribute to the hyperinflammation experienced by some individuals. The signaling pathways we uncovered can serve as a starting point for novel therapeutic strategies to alleviate tissue damage upon Chlamydia infection.