15-deoxy-Δ ^12,14 -prostaglandin J ₂ limits Salmonella infection through regulation of host TLR4 signaling and inflammasome activation

Enteric infections caused by Salmonella enterica remain a major global health concern and are increasingly associated with antimicrobial resistance. Therefore, new strategies to combat this important pathogen are needed. The interactions between S. enterica and the human host have been the subject of intense investigation over the last several decades, yet new findings continue to emerge. We previously showed that 15-deoxy-Δ ^12,14 -prostaglandin J ₂ (15d-PGJ ₂ ) reduces Salmonella colonization of macrophages, but the mechanisms underlying this protective effect were still unknown. Here, we demonstrate that 15d-PGJ ₂ limits Salmonella infection by suppressing TLR4 signaling and inflammasome activation. Treatment with 15d-PGJ ₂ reduced TLR4 expression, NF-κB activation, iNOS, COX-2, nitric oxide production, IL-1β release, and inflammasome-related targets, including NLRP3 and caspase-1 activity, while only partially reversing macrophage polarization. Combined treatment with the TLR4 antagonist TAK-242 further reduced bacterial colonization of and IL-1β release by macrophages, supporting the involvement of TLR4 signaling in the effects of 15d-PGJ ₂ . During mouse infections, 15d-PGJ ₂ reduced bacterial burdens in a tissue-dependent manner. Together, these findings demonstrate that 15d-PGJ ₂ limits Salmonella infection through selective modulation of TLR4 signaling and inflammasome activation.