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

Author(s)

Gustavo Henrique Oliveira da Rocha

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2022-01-28

Examining board members

Sandra Helena Poliselli Farsky; William Tadeu Lara Festuccia; Rodrigo Azevedo Loiola

• Advisor: Sandra Helena Poliselli Farsky

Abstract

Ulcerative colitis, alongside Crohns disease, is a chronic inflammatory bowel disease (IBD) which afflicts thousands of people worldwide, reducing overall quality of life and burdening health care systems. Available pharmacotherapy for treatment of these diseases is limited and cost-intensive and not all causes for their ethiology are known, but it is widely accepted that deregulation of inflammatory proccesses is essential for their progression. Factors such as annexin A1 (AnxA1), a glucocorticoid-mediated anti-inflammatory protein, and peroxisome proliferator activated receptor gamma (PPARy), a nuclear receptor which modulates energy metabolism and inflammation, have been studied as potential molecular targets for control of inflammation on IBDs. Thus, the present work investigated the correlation between AnxA1 and PPARy actions upon inflammation in a experimental colitis model. For such, wild type (WT) and AnxA1 knockout (AnxA1-/- ) C57BL/6 mice, and also RAW 264.7 cells transfected with shRNA for reduction of AnxA1 expression, were used. Mice were subjected to a dextran sodium sulfate induced (DSS) experimental colitis model, and RAW 264.7 cells were used in a lypopolysaccharide-induced (LPS) inflammation model. Animals and cells were both treated with pioglitazone (PPARy agonist), as well as with blockers of AnxA1 receptors in order to assess whether AnxA1 modulates the anti-inflammatory actions of PPARy and vice-versa. Data obtained evidenced that: 1) pioglitazone is unable to attenuate experimental colitis symptoms in mice when carried out up to day 10, but is able to do so when carried out up to day 6, and such effect is dependent of AnxA1; 2) pioglitazone attenuates inflammation induced by LPS in RAW 264.7 cells, and such effect is dependent on endogenous AnxA1, regardless of actions on AnxA1 receptors. Altogether, these findings evidenced pioglitazone is xiv able to attenuate inflammation during experimental colitis relying upon endogenous AnxA1, both in vivo and in vitro. Thus, we demonstrate there is an interaction between AnxA1 and PPARy during control of inflammation in experimental colitis, allowing future research aiming to elucidate therapeutic efficacy of PPARy ligands on treatment of IBDs to be carried out on more solid ground, better elucidating molecular proccesses related to the actions of such ligands which might rely on AnxA1. (AU)

• FAPESP's process: 17/05430-4 - Effects of the interaction between annexin A1 and PPAR gamma upon development of experimental colitis
• Grantee: Gustavo Henrique Oliveira da Rocha
• Support Opportunities: Scholarships in Brazil - Doctorate