title: Disparate roles of marrow- and parenchymal cell-derived TLR4 signaling in murine LPS-induced systemic inflammation.
abstract: Systemic inflammatory response syndrome (SIRS) occurs in a range of infectious and non-infectious disease processes. Toll-like receptors (TLRs) initiate such responses. We have shown that parenchymal cell TLR4 activation drives LPS-induced systemic inflammation; SIRS does not develop in mice lacking TLR4 expression on parenchymal cells. The parenchymal cell types whose TLR4 activation directs this process have not been identified. Employing a bone marrow transplant model to compartmentalize TLR4 signaling, we characterized blood neutrophil and cytokine responses, NF-κB1 activation, and Tnf-α, Il6, and Ccl2 induction in several organs (spleen, aorta, liver, lung) near the time of LPS-induced symptom onset. Aorta, liver, and lung gene responses corresponded with both LPS-induced symptom onset patterns and plasma cytokine/chemokine levels. Parenchymal cells in aorta, liver, and lung bearing TLR4 responded to LPS with chemokine generation and were associated with increased plasma chemokine levels. We propose that parenchymal cells direct SIRS in response to LPS.
authors.affiliation: Mayo Graduate School, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Juskewitch
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Platt
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Knudsen
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Brunn
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002450:Cell Communication; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009195:Peroxidase