TLR4 signaling selectively and directly promotes CGRP release from Vagal afferents in the mouse

Lin Jia, Syann Lee, Jessica A. Tierney, Joel K. Elmquist, Michael D. Burton, Laurent Gautron

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

There has been a long-standing debate regarding the role of peripheral afferents in mediating rapid-onset anorexia among other responses elicited by peripheral inflammatory insults. Thus, the current study assessed the sufficiency of peripheral afferents expressing toll-like receptor 4 (TLR4) to the initiation of the anorexia caused by peripheral bacterial lipopolysaccharide (LPS). We generated a Tlr4 null (Tlr4LoxTB) mouse in which Tlr4 expression is globally disrupted by a loxP-flanked transcription blocking (TB) cassette. This novel mouse model allowed us to restore the endogenous TLR4 expression in specific cell types. Using Zp3-Cre and Nav1.8-Cremice, we produced mice that express TLR4 in all cells (Tlr4LoxTB X Zp3-Cre) and in peripheral afferents (Tlr4LoxTB X Nav1.8-Cre), respectively. We validated the Tlr4LoxTB mice, which were phenotypically identical to previously reported global TLR4 knock-out mice. Contrary to our expectations, the administration of LPS did not cause rapid-onset anorexia in mice with Nav1.8-restricted TLR4. The later result prompted us to identify Tlr4-expressing vagal afferents using in situ hybridization (ISH). In vivo, we found that Tlr4 mRNA was primarily enriched in vagal Nav1.8 afferents located in the jugular ganglion that co-expressed calcitonin gene-related peptide (CGRP). In vitro, the application of LPS to cultured Nav1.8-restricted TLR4 afferents was sufficient to stimulate the release of CGRP. In summary, we demonstrated using a new mouse model that vagally-expressed TLR4 is selectively involved in stimulating the release of CGRP but not in causing anorexia.

Original languageEnglish (US)
Article numberENEURO.0254-20.2020
Pages (from-to)1-16
Number of pages16
JournaleNeuro
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • Cre-loxP
  • Innate immunity
  • Neuropeptide
  • Vagus nerve

ASJC Scopus subject areas

  • Neuroscience(all)

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