title: Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages.
abstract: 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.
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.
authors.forename: Mariona
authors.initials: M
authors.lastname: Baliu-Piqué
authors.forename: Gabriela
authors.initials: G
authors.lastname: Jusek
authors.forename: Bernhard
authors.initials: B
authors.lastname: Holzmann
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000276:immunology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000276:immunology
chemical_list: C555318:CRTC3 protein, mouse; C492004:Creb1 protein, mouse; C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C556062:IL10 protein, mouse; C493487:Tlr4 protein, mouse; C505915:Tnfsf14 protein, mouse; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D016753:Interleukin-10; D016899:Interferon-beta; D015740:Calcitonin Gene-Related Peptide
keywords: CREB; Calcitonin gene-related peptide (CGRP); IL-10; Regulatory macrophages