Antigen Receptor for Chemokines Migration through the Decoy Receptor Duffy CXCL1 Inhibits Airway Smooth Muscle Cell

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 non-signaling 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 a. Interestingly, DARC-or heat shock protein 90 subunit a–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. S tructural cell migration is a central mechanism involved in a range of physiological conditions, such as wound healing (1), neurogenesis (2), and embryogenesis (3). This very fundamental mechanism may have detrimental consequences for tissue structure and function when migration leads to an excessive accumulation of cells. Tissue fibrosis (4), inappropriate angio-genesis (5), cancer cell metastasis (6), and increased airway smooth muscle mass in asthma (7) are a few examples of progressively disproportionate cell migration. Attempts have been made to understand the source of migrating cells (8–12) with the hope of better understanding the role of migration in diseases such as asthma, where the origins of migrating cells are not known in vivo (13) and, hence, cannot be specifically targeted. However, regardless of the origins of migrating cells, active recruitment of cells from different sites, near or far, is central for disease chronicity and severity (8, 14). Therefore, it is possible to speculate that interference with the machinery of cell migration, without affecting cellular viability, would disrupt the active recruitment of cells, potentially providing an avenue for therapeutic intervention. Recently, we demonstrated that IL-17–induced CXC chemo-kines, also known as growth-related oncogenes (GROs), CXCL1 (GRO-a), CXCL2 (GRO-b), and CXCL3 (GROg), had the potential to collectively induce ASMC migration (15). Although primarily known as a potent inducer of neutrophil chemotaxis (16), CXCL1 …