Pioglitazone-Mediated Attenuation of Experimental Colitis Relies on Cleaving of Annexin A1 Released by Macrophages

Autor(es)

da Rocha, Gustavo Henrique Oliveira ^[1] ; de Paula-Silva, Marina ^[1] ; Broering, Milena Fronza ^[1] ; Scharf, Pablo Rhasan dos Santos ^[1] ; Matsuyama, Larissa Satiko Alcantara Sekimoto ^[1] ; Maria-Engler, Silvya Stuchi ^[1] ; Farsky, Sandra Helena Poliselli ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN PHARMACOLOGY; v. 11, DEC 21 2020.
• Citações Web of Science: 0

Resumo

Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases (IBDs) which burden health systems worldwide; available pharmacological therapies are limited and cost-intensive. Use of peroxisome proliferator activated-receptor gamma (PPAR gamma) ligands for IBD treatment, while promising, lacks solid evidences to ensure its efficacy. Annexin A1 (AnxA1), a glucocorticoid-modulated anti-inflammatory protein, plays a key role on IBD control and is a potential biomarker of IBD progression. We here investigated whether effects of pioglitazone, a PPAR gamma ligand, rely on AnxA1 actions to modulate IBD inflammation. Experimental colitis was evoked by 2% dextran sodium sulfate (DSS) in AnxA1 knockout (AnxA1(-/-)) or wild type (WT) C57BL/6 mice. Clinical and histological parameters were more severe for AnxA(-/-) than WT mice, and 10 mg/kg pioglitazone treatment attenuated disease parameters in WT mice only. AnxA1 expression was increased in tissue sections of diseased WT mice, correlating positively with presence of CD68(+) macrophages. Metalloproteinase-9 (MMP-9) and inactive 33 kDa AnxA1 levels were increased in the colon of diseased WT mice, which were reduced by pioglitazone treatment. Cytokine secretion, reactive oxygen species generation and MMP-9 expression caused by lipopolysaccharide (LPS) treatment in AnxA1-expressing RAW 264.7 macrophages were reduced by pioglitazone treatment, effects not detected in AnxA1 knockdown macrophages. LPS-mediated increase of AnxA1 cleaving in RAW 264.7 macrophages was also attenuated by pioglitazone treatment. Finally, pioglitazone treatment increased extracellular signal-regulated kinase (ERK) phosphorylation in AnxA1-expressing RAW 264.7 macrophages, but not in AnxA1-knockdown macrophages. Thus, our data highlight AnxA1 as a crucial factor for the therapeutic actions of pioglitazone on IBDs. (AU)

• Processo FAPESP: 16/19682-2 - Mecanismos de ação da anexina A1 na doença intestinal inflamatória tratada com infliximabe
• Beneficiário: Marina de Paula Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/05430-4 - Efeitos da interação entre anexina A1 e PPAR gama sobre o desenvolvimento de colite experimental
• Beneficiário: Gustavo Henrique Oliveira da Rocha
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/07328-4 - Identificação de vias endógenas para o controle da inflamação
• Beneficiário: Sandra Helena Poliselli Farsky
• Modalidade de apoio: Auxílio à Pesquisa - Temático