TLRs and microbial infection in the liver

The liver is a target of a wide range of microbes including Listeria monocytogenes (L. monocytogenes), Salmonella and Plasmodium species. L. monocytogenes is a Gram-positive facultative intracellular bacterium which infects hepatocytes and Kupffer cells, leading to bacterial replication and the destruction of the host cell. L. monocytogenes-infected Kupffer cells produce proinflammatory cytokines, such as TNF-a and IL-12 via TLR2/MyD88-dependent signaling. In MyD88-deficient mice, proinflammatory cytokine production and L. monocytogenes clearance from host are almost abolished causing high mortality. In TLR2-deficient mice, the levels of proinflammatory cytokines are decreased, but L. monocytogenes clearance is almost identical to that observed in WT mice. The discrepancy in L. monocytogenes eradication between TLR2-deficient and Myd88-deficient mice suggests that TLR2 is involved in cytokine production in response to L. monocytogenes, but that the activation of multiple TLRs is required to achieve L. monocytogenes eradication [26].

Concerning Salmonella infection TLR4-mutated C3H/HeJ mice display an enhanced susceptibility to S. typhimurium [63, 64]. Functional TLR4 is required to upregulate TLR2 mRNA, downregulate TLR4 mRNA and initiate granuloma for mation in the liver [65]. Furthermore, C3H/HeJ mice show an impairment in their NO-dependent antimicrobial activity and display high levels of S. typhimurium in Kupffer cells [64]. S. choleraesuis infection induces liver injury through upregulation of Fas-ligand on NKT cells which is dependent on TLR2, but not TLR4 [66]. However, in this model of liver injury, eradication of S. choleraesuis does not depend on TLR2 and TLR4, suggesting that Salmonella infection may activate other TLRs in addition to TLR2 and TLR4.

Plasmodium berghei, a lethal strain of mouse malaria, induces stage-specific pathological changes in the host including asymptomatic changes during the liver stage and symptomatic changes during the erythrocyte stage, characterized by the presence of apoptotic and necrotic hepatocytes and dense infiltration of lymphocytes. Liver injury in this model is mediated by infiltrating lymphocytes in response to increased IL-12 production. In mice deficient in MyD88, IL-12 secretion and liver injury are completely blunted suggesting that the TLR-MyD88 pathway is an essential mediator of hepatic manifestations of malaria infection [67].

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