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.

The Duffy antigen receptor for chemokines regulates asthma pathophysiology

“…Indeed, the effect on neutrophils was rather small and conflicts with previous findings suggesting that neutrophils promote AHR . Although recent in vitro findings suggest that loss of DARC promotes CXCL1‐induced ASM proliferation, we did not detect an effect of DARC on α ‐smooth muscle actin mRNA or any other markers of airway remodelling. Although we cannot rule out that the relatively short exposure period (3 weeks) may be insufficient to detect an effect of DARC on airway remodelling, we were able to detect an effect of AHR at this time‐point.…”

“…5 Although any causal link has yet to be determined, DARC is expressed on several cells relevant to asthma such as erythrocytes, lung endothelial cells, alveolar epithelial cells 6 and airway smooth muscle (ASM) cells. 7 Erythrocyte DARC internalizes circulating cytokines which prevents the interaction between cytokines and leucocytes. 8 In contrast, endothelial DARC promotes chemokine transcytosis and subsequent leucocyte migration into organs.…”

CXCL6 is an important paracrine factor in the pro-angiogenic human cardiac progenitor-like cell secretome

“…GROa is a proinflammatory cytokine/chemokine involved in angiogenesis that signals through the G protein-coupled receptor CXCR2. In certain contexts, GROa can also act as an inhibitor of migration, as is the case in human primary airway smooth muscle cells 42 . Plasma GROa levels correlate inversely with severity of disease in an experimental murine model of myocarditis 43 .…”

Overview and potential unifying themes of the atypical chemokine receptor family

“…3A and B). Exceptions are represented by ackr5, which has not been investigated in this respect, and ACKR1, which has been shown to induce ERK1/2 phosphorylation in human airway smooth muscle cells whose expression of b-arrestins is debated [122,164,165]. Noteworthy, each ACKR shows a unique b-arrestin recruitment pattern, as ACKR2 and ACKR3 selectively recruit b-arrestin1 and b-arrestin2, respectively, whereas ACKR4 recruits both b-arrestins (see Fig.…”