Cigarette Smoke Increases Endothelial CXCL16-Leukocyte CXCR6 Adhesion In Vitro and In Vivo. Potential Consequences in Chronic Obstructive Pulmonary Disease

Abstract

Cardiovascular disease (CVD) is a major comorbidity in chronic obstructive pulmonary disease (COPD). Although the mechanism of its development remains largely unknown, it appears to be associated with cigarette consumption and reduced lung function. Therefore, the aim of this study was to investigate the potential link between water-soluble cigarette smoke extract (CSE)-induced endothelial dysfunction and the function of CXCL16/CXCR6 axis on the initial attachment of leukocytes, in addition to its possible impact on COPD-associated systemic inflammation. To do this, we employed several experimental approaches, including RNA silencing and flow cytometry analysis, the dynamic flow chamber technique, and intravital microscopy in the cremasteric arterioles of animals exposed to cigarette smoke (CS). CSE-induced arterial CXCL16 expression, leading to increased platelet–leukocyte and mononuclear cell adhesiveness. CSE-induced CXCL16 expression was dependent on Nox5 expression and subsequent RhoA/p38 MAPK/NF-κB activation. Flow cytometry analysis revealed that COPD patients (n = 35) presented greater numbers of activated circulating platelets (PAC-1+ and P-selectin+) expressing CXCL16 and CXCR6 as compared with age-matched controls (n = 17), with a higher number of CXCR6+-platelets in the smoking COPD group than in ex-smokers. This correlated with enhanced circulating CXCR6+-platelet–leukocyte aggregates in COPD patients. The increase in circulating numbers of CXCR6-expressing platelets and mononuclear cells resulted in enhanced platelet–leukocyte and leukocyte adhesiveness to CSE-stimulated arterial endothelium, which was greater than that found in age-matched controls and was partly dependent on endothelial CXCL16 upregulation. Furthermore, CS exposure provoked CXCL16-dependent leukocyte–arteriolar adhesion in cremasteric arterioles, which was significantly reduced in animals with a nonfunctional CXCR6 receptor. In conclusion, we provide the first evidence that increased numbers of CXCR6-expressing circulating platelets and mononuclear leukocytes from patients with COPD might be a marker of systemic inflammation with potential consequences in CVD development. Accordingly, CXCL16/CXCR6 axis blockade might constitute a new therapeutic approach for decreasing the risk of CVD in COPD patients.

Kinetics of the accumulation of group 2 innate lymphoid cells in IL-33-induced and IL-25-induced murine models of asthma: a potential role for the chemokine CXCL16

“…3, in sections of lung tissue from the challenged mice, CXCL16 was immunolocalized principally in the epithelial cells of the airway and also in some submucosal mononuclear cells and vascular endothelial cells. 22 OVA, IL-25, and IL-33 challenge induced elevated expression of CXCL16 at day 19, consistent with the ELISA data above.…”

Novel Immune Features of the Systemic Inflammation Associated with Primary Hypercholesterolemia: Changes in Cytokine/Chemokine Profile, Increased Platelet and Leukocyte Activation

“…Furthermore, platelets seem to be critical for leukocyte adhesion to dysfunctional (stimulated) arterial endothelium, as leukocyte-endothelium interactions were significantly impaired when platelets were dissociated with EDTA. It is widely accepted that activated platelets can mediate the endothelial adhesion of circulating leukocytes, a characteristic feature of the dysfunctional endothelium [14,28,29,30,31]. We also found a significant enhancement in the percentage of platelet-leukocyte aggregates, which were established with almost all the leukocyte subsets investigated in a background of PH.…”

Increased eryptosis in smokers is associated with the antioxidant status and C-reactive protein levels

“…Manzur-Jattin et al (2016) have indicated that erythrocyte eryptotic forms such as stomatocytes and spherocytes, exposing phosphatidylserine out of the membrane have higher chance to adhere to endothelium through the transmembrane chemokine CXCL16 (Borst et al, 2012), eventually promoting thrombus formation. In this context, it has recently been reported that cigarette smoke increases endothelial CXCL16-leukocyte CXCR6 adhesion in vitro and in vivo (Marques et al, 2017).…”