Role of toll-like receptor 4 in macrophage activation and tolerance during Salmonella enterica serovar typhimurium infection

Toll-like receptors (TLRs) play an important role in the innate immune response, particularly in the initial interaction between the infecting microorganism and phagocytic cells, such as macrophages. We investigated the role of TLR4 during infection of primary murine peritoneal macrophages with Salmonella enterica serovar Typhimurium. We found that macrophages from the C3H/HeJ mouse strain, which carries a functionally inactive Tlr4 gene, exhibit marked impairment of tumor necrosis factor alpha (TNF-alpha) secretion in response to S. enterica serovar Typhimurium infection. However, activation of extracellular growth factor-regulated kinase and NF-kappaB signaling pathways was relatively unaffected, as was increased expression of TNF-alpha mRNA. Furthermore, macrophage tolerance, which is associated with increased expression of the NF-kappaB p50 and p52 subunits, was induced by S. enterica serovar Typhimurium even in the absence of functional TLR4. These results indicate that during infection of macrophages by S. enterica serovar Typhimurium, TLR4 signals are required at a posttranscriptional step to maximize secretion of TNF-alpha. Signals delivered by pattern recognition receptors other than TLR4 are sufficient for the increased expression of the TNF-alpha transcript and at least some genes associated with macrophage tolerance.