Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor-and sepsis-induced cytokine storm

Haitao Wen, Yu Lei, So Young Eun, Jenny P.Y. Ting

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


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 (semaphoring 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 rle of plexins to TLR signaling and suggest plexin-A4 and Sema3A as new intervention points for treating sepsis.

Original languageEnglish (US)
Pages (from-to)2943-2957
Number of pages15
JournalJournal of Experimental Medicine
Issue number13
StatePublished - Dec 20 2010
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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