Abstract
Impaired intestinal mucosal integrity during colitis involves the peroxisome proliferator-activated receptor-γ (PPARγ), an important anti-inflammatory factor in intestinal mucosa homoeostasis, which is a potential target in colitis. Recurrent chronic pain is a vital pathogenetic feature of colitis. Nevertheless, potential functions of PPARγ in the colitis-associated hyperalgesia remain unclear. This study aimed to investigate biological roles of pioglitazone in relieving colitis-associated pain hypersensitivity by a PPARγ tight junction protein-dependent mechanism during the course of dextran sodium sulfate (DSS)-induced intestinal inflammation. The DSS-induced colitis model was generated in C57BL/6 mice. Changes in colitis induced the injury of intestinal mucosal barrier and hyperalgesia after a 6-day treatment of pioglitazone (25 mg/kg, IP injection) were assessed through immunofluorescent, hematoxylin and eosin (H&E) staining, western blot analysis, and determination of paw withdrawal mechanical threshold. A significant reduction of paw withdrawal mechanical threshold occurred after DSS treatment. Follow-up data showed that systematic administration of PPARγ agonist pioglitazone ameliorated the DSS-induced colitis and the development of colitis-associated hyperalgesia by repairing the intestinal mucosal barrier. The tight junction proteins ZO-1 and Claudin-5 were upregulated by PPARγ signaling, which in turn promoted the improvement of intestinal barrier function. Moreover, pioglitazone inhibited phosphorylation of ERK and NF-κB in the colon and decreased the levels of inflammatory cytokines in both colon spine tissues. Furthermore, systemically pioglitazone treatment inhibited the activation of microglia and astrocytes, as well as DSS-induced phosphorylation of NR2B subunit in spinal cord, which was correspondingly consistent with the pain behavior. Pioglitazone ameliorates DSS-induced colitis and attenuates colitis-associated mechanical hyperalgesia, with improving integrity of the intestinal mucosal barrier by directly upregulating tight junction proteins. The PPARγ-tight junction protein signaling might be a potential therapeutic target for the treatment of colitis-associated chronic pain.
Highlights
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are characterized by diarrhea, weight loss, and chronic pain
These results suggested that peroxisome proliferator-activated receptor-γ (PPARγ) in the colon participates in the progression of acute intestinal inflammation
This study demonstrated that systematic administration of pioglitazone, an agonist of PPARγ, could alleviate dextran sodium sulfate (DSS)-induced colitis, attenuate colitis-associated mechanical hyperalgesia, and improve integrity of the intestinal mucosal barrier by directly upregulating tight junction proteins
Summary
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are characterized by diarrhea, weight loss, and chronic pain. IBD result in debilitating illness [1], among which chronic pain [2] emerges from the hyperresponsiveness of neuronal, immune, and endocrine signaling pathways within the intestines, the peripheral [3], and the central nervous system [4]. The mechanisms involved in IBD-associated chronic pain encompass neuronal synaptic changes couple with increased neurotransmitter release [5]. The mechanisms in the inflammatory intestinal wall include interactions of immune cells, macrophages, smooth muscles, and enteric glias [6,7,8,9]. Upon epithelial injury and intestinal inflammation in IBD, compromised intestinal barrier integrity subsequently arises, dysregulated transportation of water and ion, exposures of immune cells to bacterial antigens, and triggers reactive enteric gliosis. Tight junctions are pivotal in regulating intestinal permeability and maintaining intestinal barrier integrity. Emerging evidences from experimental intestinal inflammation models have supported the idea that a strong connection exists between tight junction protein impairment and intestinal inflammation [11, 13]
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