Ajayi Ayodeji Samuel, Gerkins Claire, Fragoso Gabriela, Calvé Annie, Santos Manuela M
Nutrition and Microbiome Laboratory, Institut du Cancer de Montréal, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
Front Immunol. 2025 Jul 28;16:1614466. doi: 10.3389/fimmu.2025.1614466. eCollection 2025.
Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract that frequently requires long-term immunosuppressive therapy, which increases the risk of infections and other complications. During active disease, intestinal bleeding is common and leads to the release of free luminal heme, a pro-inflammatory molecule that can disrupt mucosal integrity, fuel microbial dysbiosis, and amplify inflammation. Interleukin-22 (IL-22) plays a protective role in the gut by promoting epithelial barrier integrity and wound healing. More recently, IL-22 has been shown to induce hemopexin, a heme scavenger protein that limits heme availability and suppresses bacterial growth during systemic infections.
Here we investigate the protective role of IL-22 and hemopexin in the context of colitis using the dextran sodium sulphate (DSS) acute colitis model in mice. Wild-type (Wt) and mice were used to evaluate the effects of exogenous hemopexin and hemin treatments on colitis severity.
IL-22 signaling was crucial for the induction of hemopexin in the colon, as mice exhibited limited hemopexin induction and more severe colitis, which could be reversed by recombinant hemopexin administration. Additionally, hemin treatment, known to upregulate heme oxygenase-1 (HO-1), failed to show full protective effects in mice, suggesting that IL-22 signaling contributes to the anti-inflammatory and antioxidant effects of hemin by inducing hemopexin and HO-1.
These findings reveal a critical protective role for IL-22 by increasing the amount of hemopexin and HO-1 production in the colon, which could be part of a protective mechanism that mitigates DSS-induced colonic inflammation. Given its epithelial-specific and immunomodulatory activity, IL-22 represents a promising therapeutic approach for IBD. Furthermore, hemopexin itself may serve as an adjunct therapy during active disease.
炎症性肠病（IBD）是一种胃肠道的慢性复发性炎症性疾病，常需要长期免疫抑制治疗，这会增加感染及其他并发症的风险。在疾病活动期，肠道出血很常见，并导致肠腔内游离血红素的释放，血红素是一种促炎分子，可破坏黏膜完整性、助长微生物生态失调并放大炎症。白细胞介素-22（IL-22）通过促进上皮屏障完整性和伤口愈合在肠道中发挥保护作用。最近，IL-22已被证明可诱导血浆铜蓝蛋白，这是一种血红素清除蛋白，在全身感染期间可限制血红素的可用性并抑制细菌生长。
在此，我们使用葡聚糖硫酸钠（DSS）急性结肠炎小鼠模型研究IL-22和血浆铜蓝蛋白在结肠炎中的保护作用。使用野生型（Wt）和 小鼠评估外源性血浆铜蓝蛋白和血红素处理对结肠炎严重程度的影响。
IL-22信号传导对于结肠中血浆铜蓝蛋白的诱导至关重要，因为 小鼠表现出有限的血浆铜蓝蛋白诱导和更严重的结肠炎，这可通过给予重组血浆铜蓝蛋白来逆转。此外，已知可上调血红素加氧酶-1（HO-1）的血红素处理在 小鼠中未显示出完全的保护作用，这表明IL-22信号传导通过诱导血浆铜蓝蛋白和HO-1促进血红素的抗炎和抗氧化作用。
这些发现揭示了IL-22通过增加结肠中血浆铜蓝蛋白和HO-1的产生发挥关键保护作用，这可能是减轻DSS诱导的结肠炎症的保护机制的一部分。鉴于其上皮特异性和免疫调节活性，IL-22是一种有前景的IBD治疗方法。此外，血浆铜蓝蛋白本身可在疾病活动期用作辅助治疗。
