Salmonella disrupts lymph node architecture by TLR4-mediated suppression of homeostatic chemokines.
We report that infection of draining lymph nodes (DLNs) by Salmonella typhimurium results in the specific downregulation of the homeostatic chemokines CCL21 and CXCL13, which are essential for normal DLN organization and function. Our data reveal that the mechanism of this suppression is dependent on S. typhimurium LPS (sLPS). The decrease in CCL21 expression involves interaction between sLPS and CCL21-producing cells within DLNs, triggering a distinct Toll-like receptor 4 (TLR4)-mediated host signaling response. In this response, suppressor of cytokine signaling-3 (Socs3) is upregulated, which negatively regulates mothers against decapentaplegic homolog-3 (Smad3)-initiated production of CCL21. Disruption of lymph node architecture and cellular trafficking enhances S. typhimurium virulence and could represent a mechanism of immune suppression used by pathogens that primarily target lymphoid tissue.
St John
Ashley L
AL
Department of Immunology, Duke University Medical Center, Durham, NC, USA.
Abraham
Soman N
SN
D000217:Acyltransferases / Q000235:genetics; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics; D005434:Flow Cytometry; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000473:pathology*; D012486:Salmonella typhimurium; D015398:Signal Transduction / Q000276:immunology; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D029968:Escherichia coli Proteins; D008070:Lipopolysaccharides; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000217:Acyltransferases; C097895:MsbB protein, E coli