Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages

Eur J Immunol. 2014 Dec;44(12):3708-16. doi: 10.1002/eji.201444553. Epub 2014 Nov 10.


Environmental signals shape the phenotype and function of activated macrophages. Here, we show that the neuropeptide calcitonin gene-related peptide (CGRP), which is released from sensory nerves, modulates the phenotype of TLR4-activated murine macrophages by enhancing expression of the regulatory macrophage markers IL-10, sphingosine kinase 1 (SPHK1), and LIGHT (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes). In contrast, CGRP inhibits production of cytokines characteristic of inflammatory macrophages and does not affect expression of wound-healing macrophage markers upon TLR4 engagement. In IL-4-stimulated macrophages, CGRP increased LIGHT expression, but failed to induce IL-10 and SPHK1. The stimulatory effect of CGRP on IL-10 production required activation of protein kinase A and was linked to prolonged phosphorylation of CREB and sustained nuclear accumulation of CRTC2 and CRTC3 (where CRTC is CREB-regulated transcriptional cofactor). CGRP enhanced expression of regulatory macrophage markers during the early, but not late, phase of LPS-stimulation and this effect was independent of autocrine type-I IFN activity. In contrast, autocrine type-I IFN activity and treatment of macrophages with IFN-β promoted late-phase IL-10 production, but had only minor influence on LIGHT and SPHK1 expression. Together, the results identify neuroimmunological communication through CGRP as a novel costimulatory pathway promoting the development of a regulatory phenotype of TLR4-stimulated macrophages. CGRP appears to act through a mechanism that involves sustained activation of CREB-dependent gene transcription.

Keywords: CREB; Calcitonin gene-related peptide (CGRP); IL-10; Regulatory macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / genetics
  • Calcitonin Gene-Related Peptide / immunology*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / immunology
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Macrophage Activation / physiology*
  • Macrophages / cytology
  • Macrophages / immunology*
  • Mice
  • Mice, Knockout
  • Phosphorylation / genetics
  • Phosphorylation / immunology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transcription, Genetic / genetics
  • Transcription, Genetic / immunology
  • Tumor Necrosis Factor Ligand Superfamily Member 14 / genetics
  • Tumor Necrosis Factor Ligand Superfamily Member 14 / immunology


  • CRTC3 protein, mouse
  • Creb1 protein, mouse
  • Crtc2 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • IL10 protein, mouse
  • Tlr4 protein, mouse
  • Tnfsf14 protein, mouse
  • Toll-Like Receptor 4
  • Transcription Factors
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Interleukin-10
  • Interferon-beta
  • Calcitonin Gene-Related Peptide