Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3.,Mucosal Immunology

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Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2019-12-02 , DOI: 10.1038/s41385-019-0237-2
Ian M Cartwright _{1,

2,

3} , Valerie F Curtis _{1,

2} , Jordi M Lanis _{1,

2} , Erica E Alexeev _{1,

2} , Nichole Welch _{1,

2} , Matthew S Goldberg _{1,

2} , Rachel E M Schaefer _{1,

2} , Rachel Y Gao _{1,

2} , Carlene Chun _{1,

2} , Blair Fennimore _{1,

2} , Joseph C Onyiah _{1,

2,

3} , Mark E Gerich _{1,

2} , Peter J Dempsey _{1,

4} , Sean P Colgan _{1,

2,

3}

Affiliation

Acute intestinal inflammation includes the early accumulation of neutrophils (PMN). Based on recent evidence that PMN infiltration "imprints" changes in the local tissue environment through local oxygen depletion and the release of adenine nucleotides, we hypothesized that the interaction between transmigrating PMN and intestinal epithelial cells (IECs) results in inflammatory acidification of the tissue. Using newly developed tools, we revealed that active PMN transepithelial migration (TEM) significantly acidifies the local microenvironment, a decrease of nearly 2 pH units. Using unbiased approaches, we sought to define acid-adaptive pathways elicited by PMN TEM. Given the significant amount of adenosine (Ado) generated during PMN TEM, we profiled the influence of Ado on IECs gene expression by microarray and identified the induction of SLC26A3, the major apical Cl-/HCO3- exchanger in IECs. Utilizing loss- and gain-of-function approaches, as well as murine and human colonoids, we demonstrate that Ado-induced SLC26A3 promotes an adaptive IECs phenotype that buffers local pH during active inflammation. Extending these studies, chronic murine colitis models were used to demonstrate that SLC26A3 expression rebounds during chronic DSS-induced inflammation. In conclusion, Ado signaling during PMN TEM induces an adaptive tissue response to inflammatory acidification through the induction of SLC26A3 expression, thereby promoting pH homeostasis.

中文翻译：

通过中性粒细胞衍生的 SLC26A3 腺苷调节来适应炎症酸度。

急性肠道炎症包括中性粒细胞 (PMN) 的早期积累。根据最近的证据表明，PMN 浸润通过局部氧耗竭和腺嘌呤核苷酸的释放在局部组织环境中“留下印记”，我们假设迁移的 PMN 和肠上皮细胞 (IEC) 之间的相互作用导致组织的炎症酸化。使用新开发的工具，我们发现活跃的 PMN 跨上皮迁移 (TEM) 显着酸化了局部微环境，降低了近 2 个 pH 单位。我们使用公正的方法，试图定义由 PMN TEM 引发的酸适应性途径。鉴于 PMN TEM 期间产生的大量腺苷 (Ado)，我们通过微阵列分析了 Ado 对 IECs 基因表达的影响，并确定了 SLC26A3 的诱导，SLC26A3 是 IECs 中主要的顶端 Cl-/HCO3- 交换剂。利用功能丧失和获得功能的方法，以及小鼠和人类的结肠样体，我们证明 Ado 诱导的 SLC26A3 促进适应性 IECs 表型，在活动性炎症期间缓冲局部 pH 值。扩展这些研究，使用慢性小鼠结肠炎模型证明 SLC26A3 表达在慢性 DSS 诱导的炎症期间反弹。总之，PMN TEM 期间的 Ado 信号传导通过诱导 SLC26A3 表达诱导对炎症酸化的适应性组织反应，从而促进 pH 稳态。我们证明 Ado 诱导的 SLC26A3 促进适应性 IEC 表型，在活动性炎症期间缓冲局部 pH 值。扩展这些研究，使用慢性小鼠结肠炎模型证明 SLC26A3 表达在慢性 DSS 诱导的炎症期间反弹。总之，PMN TEM 期间的 Ado 信号传导通过诱导 SLC26A3 表达诱导对炎症酸化的适应性组织反应，从而促进 pH 稳态。我们证明 Ado 诱导的 SLC26A3 促进适应性 IEC 表型，在活动性炎症期间缓冲局部 pH 值。扩展这些研究，使用慢性小鼠结肠炎模型证明 SLC26A3 表达在慢性 DSS 诱导的炎症期间反弹。总之，PMN TEM 期间的 Ado 信号传导通过诱导 SLC26A3 表达诱导对炎症酸化的适应性组织反应，从而促进 pH 稳态。

更新日期：2019-12-02

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