title: CXCL1 inhibits airway smooth muscle cell migration through the decoy receptor Duffy antigen receptor for chemokines.
abstract: Airway smooth muscle cell (ASMC) migration is an important mechanism postulated to play a role in airway remodeling in asthma. CXCL1 chemokine has been linked to tissue growth and metastasis. In this study, we present a detailed examination of the inhibitory effect of CXCL1 on human primary ASMC migration and the role of the decoy receptor, Duffy AgR for chemokines (DARC), in this inhibition. Western blots and pathway inhibitors showed that this phenomenon was mediated by activation of the ERK-1/2 MAPK pathway, but not p38 MAPK or PI3K, suggesting a biased selection in the signaling mechanism. Despite being known as a nonsignaling receptor, small interference RNA knockdown of DARC showed that ERK-1/2 MAPK activation was significantly dependent on DARC functionality, which, in turn, was dependent on the presence of heat shock protein 90 subunit α. Interestingly, DARC- or heat shock protein 90 subunit α-deficient ASMCs responded to CXCL1 stimulation by enhancing p38 MAPK activation and ASMC migration through the CXCR2 receptor. In conclusion, we demonstrated DARC's ability to facilitate CXCL1 inhibition of ASMC migration through modulation of the ERK-1/2 MAPK-signaling pathway.
authors: Meakins-Christie Laboratories, Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada.
authors: Laila A
authors: LA
authors: Al-Alwan
authors: Meakins-Christie Laboratories, Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada.
authors: Ying
authors: Y
authors: Chang
authors: Meakins-Christie Laboratories, Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada.
authors: Simon
authors: S
authors: Rousseau
authors: Meakins-Christie Laboratories, Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada.
authors: James G
authors: JG
authors: Martin
authors: Meakins-Christie Laboratories, Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada.
authors: David H
authors: DH
authors: Eidelman
authors: Meakins-Christie Laboratories, Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada Qutayba.Hamid@McGill.ca.
authors: Qutayba
authors: Q
authors: Hamid
mesh_terms: D056151:Airway Remodeling / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D002464:Cell Migration Inhibition / Q000276:immunology*; D054360:Chemokine CXCL1 / Q000378:metabolism / Q000502:physiology*; D054426:Chemokine CXCL2 / Q000502:physiology; D004375:Duffy Blood-Group System / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology; D061251:Primary Cell Culture; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism / Q000502:physiology*
chemical_list: C473745:ACKR1 protein, human; D015415:Biomarkers; C499706:CXCL2 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D004375:Duffy Blood-Group System; D011956:Receptors, Cell Surface; D023063:Receptors, Interleukin-8B