Implication of CXCL5 in other pathological conditions associated to obesity-induced diabetes. − Rakyat Biologi

In addition to insulin resistance, obese diabetic patients are at high risk to develop associated pathologies, including, but not limited to atherosclerosis, retinopathies, or other inflammatory diseases. This is represented in figure 1. Interestingly, a major common feature of these pathologies is inflammation. Since CXCL5 is an inflammatory factor, and since its levels are increased in obese patients, we could speculate that CXCL5 is at the origin of obesity- associated co-morbidities. Furthermore, the CXCL5 receptor CXCR2 is expressed in cells other than muscle cells, such as endothelial, pulmonary, or intestinal epithelial cells. In this context, it is interesting the recently suggested correlation between obesity and asthma [11]. Strikingly, exacerbation of asthma has been also correlated with increased expression of both CXCL5 and its receptor CXCR2 [12]. Atherosclerosis is another obesity-related risk factor in which CXCR2 could play an important role. This receptor is found in macrophage-rich intimae in human atherosclerotic lesions, and it has been shown to have a major impact on macrophage accumulation in advanced lesions [13]. CXCR2 ligands, such as GRO-a participate in this macrophage accumulation and lesion progression, although they might not have a causative role [14], but rather contribute to disease progression. CXCL5 could also participate in this process.

Secondary to obesity-induced diabetes is the development of retinopathy. Development of diabetic retinopathy is a multifactorial process, and affects as much as 30% of type II diabetic patients. Much of the damage of retinopathy results from leakage of retinal blood vessels and inadequate retinal perfusion. [15] Sustained hyperglycemia in diabetes affects various vasoactive factors, such as vascular endothelial growth factor [16]. These factors, which are all interrelated, contribute to development of structural and functional changes in diabetic retinopathy, such as breakdown of the blood–retina barrier. Participation of CXCL5 in the development of retinopathy was suggested by the increased levels of this chemokine found in retinopathy diabetic patients [17].

Finally, but not limited to, CXCL5 could be also involved in the development of obesity-related inflammatory bowel disease. Although obesity has not been directly linked to the pathophysiology of inflammatory bowel disease (IBD), increased macrophage numbers as well as enhanced production of proinflammatory adipokines in obese patients may create a favorable environment for disease progression in intestinal inflammation and IBD [18]. Increased basal cytokine levels associated with obesity, both due to increased adipocytes numbers and size may predispose to more severe outcomes in IBD patients. Recent observations indicating that fat tissue is also associated with immune responses also suggest a link between obesity and gut inflammation [19]. The proinflammatory effects of CXCL5 are widely accepted. Furthermore, it was shown that CXCR2 plays a crucial pathophysiological role in experimental ulcerative colitis in mice [20]. In humans, a marked increase in ENA-78 has been reported in ulcerative colitis patients [21], and has been shown to be localized to colonic epithelial cells in IBD tissues [21,22]. Taken together, these observations suggest that the increased CXCL5 circulating levels observed during obesity could contribute to the development or progression of IBD.

Studies aiming to elucidate the role of WAT-secreted CXCL5 in all these obesity-related pathologies are likely to be forthcoming in the near future. Inhibiting CXCL5 secretion or function in obese individuals not only ameliorate their insulin sensitivity, but could also decrease the risk of developing other major obesity-related pathologies.