title: Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm.
abstract: Plexins and semaphorins are ligand-receptor pairs that serve as guidance molecules in the nervous system and play some roles in immunity. Plexins are similar to the Toll-like receptors (TLRs) in their evolutionary conservation from flies to mammals. By studying plexin-A4-deficient (Plxna4(-/-)) innate immune cells, in this study we show a novel influence of plexin-A4 on TLR signaling. Plxna4(-/-) cells exhibit defective inflammatory cytokine production upon activation by a spectrum of TLR agonists and bacteria. Plexin-A4 is required for TLR-induced activation of the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). Rac1 activation is accompanied by JNK (c-Jun N-terminal kinase) and NF-κB activation, culminating in TLR-induced binding of NF-κB and AP-1 to the promoters of inflammatory cytokines. Plxna4(-/-) mice are remarkably resistant to TLR agonist-induced inflammation and polymicrobial peritonitis caused by cecal ligation and puncture. Administration of a ligand of plexin-A4, Sema3A (semaphorin 3A), exacerbates the cytokine storm caused by TLR agonists and bacterial sepsis. TLR engagement can induce Sema3A expression, thus completing an autocrine loop. These findings expand the role of plexins to TLR signaling and suggest plexin-A4 and Sema3A as new intervention points for treating sepsis.
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wen
authors.forename: Yu
authors.initials: Y
authors.lastname: Lei
authors.forename: So-Young
authors.initials: SY
authors.lastname: Eun
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D001419:Bacteria / Q000254:growth & development; D002432:Cecum / Q000601:surgery; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015151:Immunoblotting; D008026:Ligation / Q000009:adverse effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010538:Peritonitis / Q000209:etiology / Q000378:metabolism / Q000382:microbiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins; C492110:Plxna4 protein, mouse; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; D051193:Toll-Like Receptors; D020830:rac1 GTP-Binding Protein