Mucosal Inflammation Program and.
Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
JCI Insight. 2024 Jun 11;9(14):e178525. doi: 10.1172/jci.insight.178525.
Neutrophils (polymorphonuclear leukocytes, PMNs) comprise a major component of the immune cell infiltrate during acute mucosal inflammation and have an important role in molding the inflammatory tissue environment. While PMNs are essential to clearance of invading microbes, the major PMN antimicrobial enzyme myeloperoxidase (MPO) can also promote bystander tissue damage. We hypothesized that blocking MPO would attenuate acute colitis and prevent the development of chronic colitis by limiting bystander tissue damage. Using the acute and chronic dextran sodium sulfate model of murine colitis, we demonstrated that MPO-deficient mice experienced less inflammation and more rapidly resolved colitis relative to wild-type controls. Mechanistic studies demonstrated that activated MPO disrupted intestinal epithelial barrier function through the dysregulation of the epithelial tight junction proteins. Our findings revealed that activated MPO chlorinates tyrosine within several tight junction proteins, thereby promoting tight junction mislocalization and dysfunction. These observations in cell models and in murine colitis were validated in human intestinal biopsies from individuals with ulcerative colitis and revealed a strong correlation between disease severity (Mayo score) and tissue chlorinated tyrosine levels. In summary, these findings implicate MPO as a viable therapeutic target to limit bystander tissue damage and preserve mucosal barrier function during inflammation.
中性粒细胞（多形核白细胞，PMN）构成急性黏膜炎症期间免疫细胞浸润的主要成分，并在塑造炎症组织环境方面发挥重要作用。虽然PMN 对于清除入侵的微生物至关重要，但主要的PMN 抗菌酶髓过氧化物酶（MPO）也可以通过促进旁观者组织损伤来促进。我们假设阻断 MPO 将通过限制旁观者组织损伤来减轻急性结肠炎并预防慢性结肠炎的发展。使用急性和慢性葡聚糖硫酸钠诱导的小鼠结肠炎模型，我们证明与野生型对照相比，MPO 缺陷型小鼠的炎症反应较轻，结肠炎的缓解速度更快。机制研究表明，激活的 MPO 通过调节上皮紧密连接蛋白破坏肠道上皮屏障功能。我们的研究结果表明，激活的 MPO 会使几个紧密连接蛋白中的酪氨酸氯化，从而促进紧密连接的错位和功能障碍。在细胞模型和小鼠结肠炎中的这些观察结果在溃疡性结肠炎患者的人类肠道活检中得到了验证，并揭示了疾病严重程度（Mayo 评分）和组织氯化酪氨酸水平之间存在很强的相关性。总之，这些发现表明 MPO 是一种可行的治疗靶点，可以在炎症期间限制旁观者组织损伤并维持黏膜屏障功能。
