Neuroendocrine nicotinic receptor activation increases susceptibility to bacterial infections by suppressing antimicrobial peptide production.
Stress mobilizes elements from the neuroendocrine system to modulate immune responses. Cholinergic stimulation via nicotinic receptor (nAchR) is a major neuroendocrine signaling axis associated with the stress response whose specific effects on the immune system are unknown. Here, we show that nAchR activation by topical agonist application or deletion of the nAChR antagonist catestatin (Chga(-/-)) reduced antimicrobial peptide (AMP) activity in skin extracts and increased susceptibility to methicillin-resistant Staphylococcus aureus and Group A Streptococcus infections. The adverse effects on AMP expression and infection were rescued by topical application of a nAChR antagonist. Stress-induced nAChR activation increased infection in wild-type, but not Chga(-/-) or cathelicidin-deficient, mice. These data identify a mechanism for the negative regulation of host-innate AMP response to infection through cholinergic activation and indicate nAChR-mediated cathelicidin dysregulation as a potential mechanism for increased susceptibility to infection following prolonged stress or nicotine use.
Radek
Katherine A
KA
VA San Diego Healthcare System, San Diego, CA 92161, USA. Electronic address: kradek1@lumc.edu.
Elias
Peter M
PM
Department of Dermatology, School of Medicine, University of California, San Francisco and VA Center, San Francisco, CA 94121, USA.
Taupenot
Laurent
L
VA San Diego Healthcare System, San Diego, CA 92161, USA; Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Mahata
Sushil K
SK
VA San Diego Healthcare System, San Diego, CA 92161, USA; Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
O'Connor
Daniel T
DT
VA San Diego Healthcare System, San Diego, CA 92161, USA; Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA; Center for Molecular Genetics, University of California at San Diego, La Jolla, CA 92093, USA.
Gallo
Richard L
RL
VA San Diego Healthcare System, San Diego, CA 92161, USA; Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000276:immunology; D053379:Chromogranin A / Q000172:deficiency; D015536:Down-Regulation; D055624:Methicillin-Resistant Staphylococcus aureus / Q000254:growth & development / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018722:Nicotinic Agonists / Q000276:immunology* / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000276:immunology* / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects*; D017192:Skin Diseases, Bacterial / Q000276:immunology*; D013291:Streptococcus / Q000254:growth & development / Q000276:immunology; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D053379:Chromogranin A; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C506155:chromogranin A, mouse; D054804:Cathelicidins