Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
J Leukoc Biol. 2022 Dec;112(6):1543-1553. doi: 10.1002/JLB.3MA0422-742R. Epub 2022 Jun 8.
Neutrophil (PMN) infiltration during active inflammation imprints changes in the local tissue environment. Such responses are often accompanied by significant extracellular acidosis that result in predictable transcriptional responses. In this study, we explore the mechanisms involved in inflammatory acidification as a result of PMN-intestinal epithelial cell (IEC) interactions. Using recently developed tools, we revealed that PMN transepithelial migration (TEM)-associated inflammatory acidosis is dependent on the total number of PMNs present during TEM and is polarized toward the apical surface. Extending these studies, we demonstrate that physical separation of the PMNs and IECs prevented acidification, whereas inhibition of PMN TEM using neutralizing antibodies enhanced extracellular acidification. Utilizing pharmaceutical inhibitors, we demonstrate that the acidification response is independent of myeloperoxidase and dependent on reactive oxygen species generated during PMN TEM. In conclusion, inflammatory acidosis represents a polarized PMN-IEC-dependent response by an as yet to be fully determined mechanism.
中性粒细胞（PMN）在活跃炎症期间的浸润会导致局部组织环境发生变化。这种反应通常伴随着明显的细胞外酸中毒，从而导致可预测的转录反应。在这项研究中，我们探讨了PMN-肠上皮细胞（IEC）相互作用导致炎症酸化的机制。使用最近开发的工具，我们揭示了PMN 跨上皮迁移（TEM）相关的炎症性酸中毒依赖于 TEM 过程中存在的PMN 的总数，并呈极化分布于顶膜表面。扩展这些研究，我们证明了PMN 和 IEC 的物理分离可防止酸化，而使用中和抗体抑制PMN TEM 则增强了细胞外酸化。利用药物抑制剂，我们证明酸化反应不依赖于髓过氧化物酶，而是依赖于PMN TEM 过程中产生的活性氧。总之，炎症性酸中毒代表了一种PMN-IEC 依赖的极化反应，其机制尚待充分确定。
