Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction.
Eosinophils cluster around airway nerves in patients with fatal asthma and in antigen-challenged animals. Activated eosinophils release major basic protein, which blocks inhibitory M2 muscarinic receptors (M2Rs) on nerves, increasing acetylcholine release and potentiating vagally mediated bronchoconstriction. We tested whether GW701897B, an antagonist of CCR3 (the receptor for eotaxin as well as a group of eosinophil active chemokines), affected vagal reactivity and M2R function in ovalbumin-challenged guinea pigs. Sensitized animals were treated with the CCR3 antagonist before inhaling ovalbumin. Antigen-challenged animals were hyperresponsive to vagal stimulation, but those that received the CCR3 antagonist were not. M2R function was lost in antigen-challenged animals, but not in those that received the CCR3 antagonist. Although the CCR3 antagonist did not decrease the number of eosinophils in lung tissues as assessed histologically, CCR3 antagonist prevented antigen-induced clustering of eosinophils along the nerves. Immunostaining revealed eotaxin in airway nerves and in cultured airway parasympathetic neurons from both guinea pigs and humans. Both IL-4 and IL-13 increased expression of eotaxin in cultured airway parasympathetic neurons as well as in human neuroblastoma cells. Thus, signaling via CCR3 mediates eosinophil recruitment to airway nerves and may be a prerequisite to blockade of inhibitory M2Rs by eosinophil major basic protein.
Fryer
Allison D
AD
Division of Pulmonary and Critical Care Medicine and Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97201, USA.
Stein
Louis H
LH
Nie
Zhenying
Z
Curtis
Damian E
DE
Evans
Christopher M
CM
Hodgson
Simon T
ST
Jose
Peter J
PJ
Belmonte
Kristen E
KE
Fitch
Erin
E
Jacoby
David B
DB
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000032:analysis / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D009474:Neurons / Q000502:physiology*; D010047:Ovalbumin / Q000276:immunology; D010275:Parasympathetic Nervous System / Q000276:immunology; D043585:Receptor, Muscarinic M2 / Q000502:physiology*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000032:analysis
C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D043585:Receptor, Muscarinic M2; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D019948:Receptors, Interleukin-4; D010047:Ovalbumin