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Abstract
TLR2 signaling plays a critical protective role against acute Listeria monocytogenes (Lm) infection by up-regulating inflammatory cytokines and promoting macrophage antimicrobial capabilities. However, the underlying mechanism by which TLR2 regulates hepatic macrophage-mediated anti-Lm immune responses remains poorly understood. In this study, we found that both the absolute number and proportion of monocyte/macrophage (Mo/MΦ) in the liver and spleen of Tlr2−/− mice were significantly lower compared to wild type mice. Changes in TLR2 signaling in both hepatocytes and Mo/MΦs were associated with the infiltration of Mo/MΦs in response to Lm-infection. Analyses by proteome profiler array and ELISA revealed that hepatocytes recruited Mo/MΦs via TLR2-dependent secretion of CCL2 and CXCL1, which was confirmed by receptor blocking and exogenous chemokine administration. Importantly, we found that TLR2 contributed to macrophage mobility in the liver through a TLR2/NO/F-actin pathway, facilitating the formation of macrophage-associated hepatic microabscesses. Moreover, TLR2 activation induced the expression of several PRRs on hepatic macrophages associated with the recognition of Lm and augmented macrophage bacterial clearance activity. Our findings provide insight into the intrinsic mechanisms of TLR2-induced Mo/MΦ migration and mobility, as well as the interaction between macrophages and hepatocytes in resistance to Lm infection.
Highlights
Listeria monocytogenes (L. monocytogenes, Lm) is a foodborne Gram-positive intracellular pathogen capable of invasion and replication in both phagocytic and non-phagocytic cells [1,2,3]
To verify the key role of TLR2 in the defense of an acute Lm infection, Wild type (WT) and Tlr2−/− mice were i.p. infected with 1 × 106 CFU of Lm
Our study further confirms the crucial role of TLR2 in host defense against Lm infection, as Lminfected Tlr2−/− mice were associated with poor survival and high bacterial loads in both the liver and spleen
Summary
Listeria monocytogenes (L. monocytogenes, Lm) is a foodborne Gram-positive intracellular pathogen capable of invasion and replication in both phagocytic and non-phagocytic cells (e.g., hepatocytes) [1,2,3]. An early study showed that while MyD88 was necessary for resistance to TLR2 Induces Monocyte/Macrophage Recruitment. Several subsequent studies have demonstrated that TLR2 is required for optimum control of Lm infection both in vitro and in vivo by enhancing the phagocytic ability of macrophages and up-regulating the production of TNFα, IL-12, NO, as well as the expression of costimulatory molecules CD40 and CD86 [6, 8, 9]. KCs undergo rapid necroptotic cell death induced by the bacterial virulence factor listeriolysin O, and they cannot directly contribute to immunity or tissue repair [10]. KC necrosis triggers the recruitment of circulating monocytes, which differentiate into monocyte-derived macrophages to compensate for KC loss [10, 11]. Monocytes emigrate from circulation into Lm infected sites, which is triggered by CCL2 (MCP-1)- and CCL7 (MCP-3)mediated stimulation of CCR2 on monocytes [12,13,14,15]
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