Effects of the interaction between annexin A1 and PPAR gamma upon development of experimental colitis

Abstract

Ulcerative colitis is a chronic disease that affects the lower gut and afflicts thousands of people worldwide, not only reducing overall living standards of patients but also burdening healthcare systems. Not all causes for the etiology of the disease are understood, but it is known that deregulation of the inflammatory process is essential for its progression. Inflammation is a biological process associated with the organism's response to injury and tissue damage and also essential for maintaining homeostasis. When exacerbated or prolonged, it can lead to the promotion of different maladies and aggravate those already on course, as seen in ulcerative colitis. Proteins such as annexin A1 (ANXA1), an essential factor for the anti-inflammatory effects of glucocorticoids, and the peroxisome proliferator activated receptor gamma (PPAR gama), a nuclear receptor that modulates metabolism and inflammation, have been studied as molecular targets for control of inflammation. Our research group has demonstrated that ANXA1 modulates the synthesis of PPAR³ and that it acts as a mediator for the actions of ANXA1 upon peripheral macrophages and microglia regarding resolution of inflammation. As both ANXA1 and PPAR gama modulate inflammation in ulcerative colitis, the aim of the present work is to investigate the correlation of ANXA1 with PPAR gama actions upon inflammation on a model of experimental ulcerative colitis and on in vitro models of inflammation. For such, C57BL/6 mice of wild type or ANXA1 knockout background, and also Caco-2 and RAW 264.7 RAW cell lines either unmodified or transfected with iRNA for the reduction of ANXA1 or PPAR gama expression, will be used. Mice will be used in an experimental colitis model induced by dextran sodium sulfate (DSS), while cell lines will be used in inflammation in vitro models induced by LPS. Mice as well as cells will be treated with Ac2-26 (peptide with mimetic ANXA1 actions) or pioglitazone (PPAR gama agonist), and also with receptor inhibitors, in order to assess if ANXA1 modulates the anti-inflammatory actions of PPAR gama and vice-versa. Therefore, we aim to elucidate through which mechanisms ANXA1 and PPAR gama control inflammation in ulcerative colitis, providing basis for future research that might seek new pharmacological targets for the treatment of intestinal inflammatory diseases.