Toll-Like Receptor 2 (TLR2) and TLR9 Play Opposing Roles in Host Innate Immunity against Salmonella enterica Serovar Typhimurium Infection

Abstract

bToll-like receptors (TLRs) are evolutionarily conserved host proteins that are essential for effective host defense against pathogens. However, recent studies suggest that some TLRs can negatively regulate immune responses. We observed here that TLR2 and TLR9 played opposite roles in regulating innate immunity against oral infection of Salmonella enterica serovar Typhimurium in mice. While TLR9 ؊/؊ mice exhibited shortened survival, an increased cytokine storm, and more severe Salmonella hepatitis than wild-type (WT) mice, TLR2 ؊/؊ mice exhibited the opposite phenomenon. Further studies demonstrated that TLR2 deficiency and TLR9 deficiency in macrophages both disrupted NK cell cytotoxicity against S. Typhimurium-infected macrophages by downregulating NK cell degranulation and gamma interferon (IFN-␥) production through decreased macrophage expression of the RAE-1 NKG2D ligand. But more importantly, we found that S. Typhimurium-infected TLR2 ؊/؊ macrophages upregulated inducible nitric oxide synthase (iNOS) expression, resulting in a lower bacterial load than that in WT macrophages in vitro and livers in vivo as well as low proinflammatory cytokine levels. In contrast, TLR9 ؊/؊ macrophages showed decreased reactive oxygen species (ROS) expression concomitant with a high bacterial load in the macrophages and in livers of TLR9؊/؊ macrophages were also more susceptible than WT macrophages to S. Typhimurium-induced necroptosis in vitro, likely contributing to bacterial spread and transmission in vivo. Collectively, these findings indicate that TLR2 negatively regulates anti-S. Typhimurium immunity, whereas TLR9 is vital to host defense and survival against S. Typhimurium invasion. TLR2 antagonists or TLR9 agonists may thus serve as potential anti-S. Typhimurium therapeutic agents. During the early stages of infection, the innate immune system serves as the first line of defense against microbial replication and spread before an adaptive response is mounted (1). As one mechanism to elicit a rapid and appropriate innate immune response against pathogen infection, pattern recognition receptors (PRRs) evolved in the host to recognize various microbial molecular patterns. In response, pathogens evolved to use many different tactics, including subversion of some of these host antimicrobial immune mechanisms, in order to ensure their multiplication, survival, and persistence in the host (2). This ongoing interplay between host innate immune responses and pathogen virulence factors largely determines the outcome of most infections.As the most widely studied PRRs, Toll-like receptors (TLRs) play a crucial role in pathogen recognition and the induction of immune responses. Currently, 11 and 13 TLRs have been identified in humans and mice, respectively. They are widely expressed on many cell types, such as macrophages, neutrophils, dendritic cells (DCs), and mucosal epithelial cells. TLR signaling results in the induction of reactive oxygen species (ROS) and the activation of the transcription factor NF-B, which in turn induce...

TLR9 limits enteric antimicrobial responses and promotes microbiota‐based colonisation resistance during Citrobacter rodentium infection

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