Deficiency of the CGRP receptor component RAMP1 attenuates immunosuppression during the early phase of septic peritonitis.
The neuropeptide CGRP contributes to the control of excessive cytokine production in endotoxemia models. However, the function of CGRP in sepsis caused by infection with viable pathogens is unknown. Here, we show that mice deficient for the CGRP receptor component RAMP1 have an improved anti-bacterial defense during the early, but not late, phase of polymicrobial septic peritonitis. The protective effect of Ramp1-deficiency was associated with reduced levels of IL-10 in plasma and peritoneal lavage fluid. Consistent with these findings, CGRP markedly increased IL-10 production of peritoneal and bone marrow-derived macrophages in response to short term stimulation with LPS in vitro. In addition, the lack of an intact CGRP receptor resulted in an increased recruitment and activation of neutrophils and caused an enhanced release of defensin-α1 in the peritoneal cavity. Considered together, our results identify the neuropeptide CGRP as a crucial immunosuppressive mediator impairing host defense during the early, but not late, phase of septic peritonitis.
Department of Surgery, Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany.
Gabriela
G
Jusek
Daniel
D
Reim
Kazutake
K
Tsujikawa
Bernhard
B
Holzmann
D000818:Animals; D001202:Ascitic Fluid / Q000276:immunology / Q000378:metabolism; D001419:Bacteria / Q000276:immunology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002478:Cells, Cultured; D023082:Defensins / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000097:blood / Q000276:immunology* / Q000382:microbiology; D058262:Receptor Activity-Modifying Protein 1 / Q000172:deficiency* / Q000235:genetics; D018805:Sepsis / Q000097:blood / Q000276:immunology* / Q000382:microbiology; D013997:Time Factors
D023082:Defensins; D008070:Lipopolysaccharides; C545505:Ramp1 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; C058181:insect defensin A; D016753:Interleukin-10; D015740:Calcitonin Gene-Related Peptide