Abstract
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 γ (PPARγ) 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 PPARγ 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.
Highlights
Ulcerative colitis and Crohn’s disease comprise inflammatory bowel diseases (IBDs), which are widespread and pose burdens to healthcare systems worldwide (Mak et al, 2020)
peroxisome proliferator activated-receptor γ (PPARγ) expression in Annexin A1 (AnxA1)−/− mice was and mice were treated with pioglitazone daily at a 10 mg/kg dose for a 6 days period
Data obtained in the present work evidence pioglitazone attenuates inflammation in vivo in a murine colitis model, and prevention of AnxA1 cleaving seems to be involved with such effect
Summary
Ulcerative colitis and Crohn’s disease comprise inflammatory bowel diseases (IBDs), which are widespread and pose burdens to healthcare systems worldwide (Mak et al, 2020). Patients suffer from diarrhea, anemia, fatigue and severe gut pain, among other symptoms, which become more intense during acute episodes, causing them to lose workdays and drastically reducing quality of life (Xu et al, 2018). Pharmacological options to treat these diseases are limited, as traditionally used drugs address only the major symptoms of inflammatory bowel diseases and fail to conduct patients to complete remission (Duijvestein et al, 2018). Biological therapies involving anti-TNFα antibodies, such as infliximab, while proven successful and better than conventional drugs, do not cause any response in about a third of patients and are very cost-intensive (Hossain et al, 2020). There is a trend nowadays for new IBD therapies to aim for objective targets in an individualized manner rather than following pre-determined therapy paradigms (e.g., aim for mucosal healing rather than “overall remission”), and the understanding of new IBD biomarkers and of how new or already existing drugs work and with which other molecules they interact on intestinal tissue becomes a necessity (Im et al, 2018; Ho et al, 2020)
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