UC San Diego

Millions of people worldwide suffer from food borne illness caused by the Salmonella bacterial species. Disease caused by Salmonella infection is more devastating and likely fatal in immunocompromised individuals or those in economically disadvantaged conditions. These infections start at the gastrointestinal epithelium and translocate subsequently into the lamina propria, where they encounter immune and inflammatory cells such as macrophages.Following infection, macrophages release pro-inflammatory cytokines, such as IL-1, to coordinate inflammatory responses that help clear the infection. We previously demonstrated that engulfment and cell motility protein 1 (ELMO1) expressed by macrophages is essential for the induction of many pro-inflammatory cytokine responses. Here, the role of ELMO1 in the regulation of IL-1 was investigated following Salmonella infection. The murine macrophage cell line J774 was stably transfected with control or ELMO1 shRNA, resulting in a 90% decrease in ELMO1 expression. In turn, cells were infected with Salmonella enterica Serovar typhimurium. Mature IL-1 levels, detected by western blot and ELISA, decreased significantly after Salmonella challenge in ELMO1-inhibited cells. Furthermore, luciferase assays showed a 2-fold increase in NFB activation, a transcription factor regulating many pro-inflammatory cytokines including IL-1b, in ELMO1 overexpressed cells. Additionally, co-transfection of ELMO1 and NOD2, a cytosolic bacteria-sensing protein, revealed an increase in NFB activation. In contrast, ELMO1 did not reproducibly regulate the post-translational activation of IL-1b by caspase 1. These results suggest ELMO1 regulates the NFB pathway and the subsequent expression of pro-inflammatory cytokines after bacterial infection. Understanding the mechanisms by which ELMO1 regulates inflammation can reveal new therapeutic targets for people suffering from chronic inflammation and related immune-mediated disorders.