Salmonella disrupts lymph node architecture by TLR4-mediated suppression of homeostatic chemokines

Ashley L St John, et al. Nature Medicine 15: 1259–1265 (2009)

Speaker: Shu-Chun Chien (簡淑珺)                              Time: 13:10~14:00, May. 19, 2010

Commentator: Dr. Chi-Chang Shieh (謝奇璋醫師)     Place: Room 601

Abstract:

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a food-borne bacterial pathogen causing gastroenteritis in the human. When S. Typhimurium infects the mouse, it could cross the gastrointestinal barrier and colonize in the lymphoid tissues including mesenteric lymph nodes (MLNs) and spleen. Although the adaptive immunity could eliminate most pathogens, it is ineffective in controlling S. Typhimurium. In this study, the authors explored how S. Typhimurium influences the lymph nodes after infection of a mouse. First, they found that the B and T cell zones of draining lymph nodes (DLNs) were disrupted by wild-type (WT) S. Typhimurium. However, the DLNs of a mouse infected by the msbB mutant, which failed to produce a modified lipopolysaccharide (LPS) that can be recognized by TLR4, remained undamaged, suggesting that the disruption of DLNs during S. Typhimurium infection is mediated by the LPS of this organism (sLPS). They further found that the DLNs of a WT S. Typhimurium-infected mouse had lower T cell numbers compared to those of a msbB mutant-infected mouse. The distributions of dendritic cells in DLNs were also strikingly different between the mice infected by these two strains. Moreover, the DLNs disruption resulted from altered cellular trafficking was associated with the decreased expression levels of CCL21 and CXCL13, two chemokines that promote the formation of T and B cell zones. Disruption of DLNs after infection by S. Typhimurium was mediated by TLR4, and Socs3 has been known to modulate the signaling downstream of TLR4¹. It has been shown previously that Socs3 could bind with the phosphorylated Smad3 (P-Smad3) in the LPS-activated macrophage, preventing the nuclear translocation of P-Smad3². Here the authors showed that this signaling pathway was activated to cause decreased level of CCL21 after S. Typhimurium infection in SVEC4-10, a cell line derived from the high endothelial venule of mouse lymph node. On the other hand, neutralization of CCL21 and CXCL13 by antibodies resulted in disruption of DLNs and increased colonization of the msbB mutant strain in the spleen and liver of a mouse. Taken together, their data suggest that when S. Typhimurium infects the host, sLPS is sensed by TLR4 on CCL21-producing cells and caused upregulation of Socs3, which in turn suppresses CCL21 production to result in the disruption of DLNs by binding with P-Smad3.

References:

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2.      Liu, X et al., Mol. Immunol. 45: 1405-1413 (2008)