Nuclear IL-33 amplifies NF-κB signaling to drive neutrophil recruitment and activation in the endocervical epithelium during Mycoplasma genitalium infection.

Mycoplasma genitalium has emerged as a clinically significant etiology of sexually transmitted infections that often establishes persistent infections within the female reproductive tract. Although the recruitment of neutrophils is a characteristic feature of the cervicitis associated with M. genitalium, the molecular mechanisms that govern this response at the mucosal interface remain incompletely defined. In this study, the infection of endocervical epithelial cells with M. genitalium was observed to induce a robust increase in IL-33 protein that localized within the nucleus. The transcriptional induction of the gene encoding IL-33 was mediated by a signaling axis involving Toll-like receptor 2 (TLR2) and TANK-binding kinase 1 (TBK1), which led to the nuclear translocation and promoter binding of Interferon Regulatory Factor 1 (IRF1) and 7 (IRF7). Within the nucleus, IL-33 physically complexed with the p65 subunit of NF-κB. This interaction facilitated the recruitment and occupancy of p65 at the promoters of the genes encoding CXCL1 and IL-8, thereby specifically amplifying the secretion of these chemokines. Functional assays demonstrated that the secretion of chemokines dependent on nuclear IL-33 was required for the adhesion, chemotaxis, and oxidative activation of neutrophils. These findings identify a pathogenic mechanism whereby M. genitalium exploits the nuclear function of IL-33 to drive chronic neutrophilic inflammation and contribute to the immunopathology of the reproductive tract.