Skip to main content
ELMO1 has an essential role in the internalization of Salmonella Typhimurium into enteric macrophages that impacts disease outcome.
- Author(s): Das, Soumita;
- Sarkar, Arup;
- Choudhury, Sarmistha Sinha;
- Owen, Katherine A;
- Castillo, Victoria;
- Fox, Sarah;
- Eckmann, Lars;
- Elliott, Michael R;
- Casanova, James E;
- Ernst, Peter B
- et al.
Published Web Locationhttps://doi.org/10.1016/j.jcmgh.2015.02.003
Backgrounds and aims4-6 million people die of enteric infections each year. After invading intestinal epithelial cells, enteric bacteria encounter phagocytes. However, little is known about how phagocytes internalize the bacteria to generate host responses. Previously, we have shown that BAI1 (Brain Angiogenesis Inhibitor 1) binds and internalizes Gram-negative bacteria through an ELMO1 (Engulfment and cell Motility protein 1)/Rac1-dependent mechanism. Here we delineate the role of ELMO1 in host inflammatory responses following enteric infection.
MethodsELMO1-depleted murine macrophage cell lines, intestinal macrophages and ELMO1 deficient mice (total or myeloid-cell specific) was infected with Salmonella enterica serovar Typhimurium. The bacterial load, inflammatory cytokines and histopathology was evaluated in the ileum, cecum and spleen. The ELMO1 dependent host cytokines were detected by a cytokine array. ELMO1 mediated Rac1 activity was measured by pulldown assay.
ResultsThe cytokine array showed reduced release of pro-inflammatory cytokines, including TNF-α and MCP-1, by ELMO1-depleted macrophages. Inhibition of ELMO1 expression in macrophages decreased Rac1 activation (~6 fold) and reduced internalization of Salmonella. ELMO1-dependent internalization was indispensable for TNF-α and MCP-1. Simultaneous inhibition of ELMO1 and Rac function virtually abrogated TNF-α responses to infection. Further, activation of NF-κB, ERK1/2 and p38 MAP kinases were impaired in ELMO1-depleted cells. Strikingly, bacterial internalization by intestinal macrophages was completely dependent on ELMO1. Salmonella infection of ELMO1-deficient mice resulted in a 90% reduction in bacterial burden and attenuated inflammatory responses in the ileum, spleen and cecum.
ConclusionThese findings suggest a novel role for ELMO1 in facilitating intracellular bacterial sensing and the induction of inflammatory responses following infection with Salmonella.
For improved accessibility of PDF content, download the file to your device.