Elafin inhibits macrophage activation by blocking a chloride channel

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-07-18 DOI:10.1016/j.bbadis.2025.167989

Xia Li , Longxin Chen , Na Chen , Liang Xu , Xiaoli Cui , Feng Wang

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引用次数: 0

Abstract

The molecular mechanisms underlying the anti-inflammatory functions of elafin, beyond its role as a serine protease inhibitor, have garnered significant interest. In this study, we engineered an antibody-elafin fusion construct (Her-elafin) by grafting elafin into the complementarity-determining region (CDR) of the Herceptin antibody. Her-elafin retained the full inhibitory activity of elafin against neutrophil elastase and effectively suppressed lipopolysaccharide (LPS)-induced macrophage activation. Using Her-elafin as a molecular probe, we identified that elafin specifically binds to and inhibits Clic1, a chloride channel expressed on macrophages. This binding likely reduces intracellular reactive oxygen species (ROS) production, thereby attenuating downstream inflammatory cascades. Furthermore, the dual inhibitory activities of Her-elafin against neutrophil elastase and Clic1 resulted in significant anti-inflammatory effects in a murine model of acute lung injury, highlighting its potential as a promising therapeutic strategy.

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Elafin通过阻断氯离子通道抑制巨噬细胞活化。

除了作为丝氨酸蛋白酶抑制剂的作用外，elafin抗炎功能的分子机制已经引起了人们的极大兴趣。在这项研究中，我们设计了一种抗体-elafin融合结构（Her-elafin），将elafin嫁接到Herceptin抗体的互补性决定区（CDR）。Her-elafin保留了elafin对中性粒细胞弹性酶的完全抑制活性，并有效抑制脂多糖（LPS）诱导的巨噬细胞活化。使用Her-elafin作为分子探针，我们发现elafin特异性结合并抑制巨噬细胞上表达的氯离子通道Clic1。这种结合可能会减少细胞内活性氧（ROS）的产生，从而减轻下游炎症级联反应。此外，Her-elafin对中性粒细胞弹性蛋白酶和Clic1的双重抑制活性在小鼠急性肺损伤模型中产生显著的抗炎作用，突出了其作为一种有前景的治疗策略的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.