烯醇化酶在急性發炎過程中對吞噬型白血球浸潤中扮演之角色

Abstract

先天性免疫反應中會觸發急炎症來對抗組織損傷和微生物侵襲，其特徵是嗜中性白血球和單核球浸潤至發炎組織中。在此過程，胞外的基質蛋白水解對於吞噬細胞遷移到發炎部位扮演重要的作用。在癌細胞和活化的單核細胞中，烯醇化酶 (enolase-1, ENO-1) 可以從細胞質轉移到表面，並作為受體與纖溶酶原 (plasminogen, PLG) 結合增強局部纖溶酶 (plasmin, PLA)的產生，促進細胞外基質降解進而使細胞遷移。因此在這項研究中，本實驗探討阻斷ENO-1是否可以改善急性炎症模型小鼠中嗜中性白血球和單核球的浸潤。首先，從結果可得知以刺激物極化成M1型態後的骨髓衍生巨噬細胞 (bone marrow-derived macrophage, BMDM)中，ENO-1在細胞表面的表達量增加。在動物模型中，由壞死所誘發腹膜炎模型，ENO-1之阻斷可改善單核球和嗜中性白血球的浸潤數量及比例。給予anti-ENO-1抗體治療可以減輕由博萊黴素 (bloemycin, Blm) 和脂多醣 (lipopolysaccharides, LPS) 所引發的急性肺部損傷及發炎中，皆能減少嗜中性白血球和單核球的進入以及降低支氣管肺泡灌洗液 (bronchoalveolar lavage fluid, BALF)中monocyte chemoattractant protein 1 (MCP-1)、interleukin (IL) -1β、tumor necrosis factor (TNF-α)、IL -6和keratinocyte chemoattractant (KC) 的含量。另外在LPS誘導的急性肺部損傷中，有效降低BALF中的細胞激素和蛋白質、DNA (deoxyribonucleic acid) 的累積，減緩了嗜中性白血球胞外陷阱 (neutrophil extracellular traps, NETs) 產生的可能性。總結，這些結果證實使用抗ENO-1抗體阻止ENO-1之功能可作為肺部急性損傷/急性呼吸窘迫綜合徵候群的潛在治療方法。

The immune system responds to tissue injury and microbial invasion by triggering an acute inflammatory response, inducing the infiltration neutrophils and monocytes to the inflamed tissue. During this process, cell surface–associated proteolysis plays a crucial role for the recruitment of leukocyte to sites of inflammation. It is known that in cancer cells and activated monocytes, the glycolytic enzyme enolase-1 (ENO-1) can translocate from cytosol to the cell surface, where it binds plasminogen and enhances plasmin production. The plasminogen activation system is a key regulator in extracellular matrix degradation and improved cell emigration. In this study, we investigated whether blocking ENO1 could ameliorate the infiltration of neutrophils and monocytes in several models of acute inflammation in mice. First, we found that cell surface expression of ENO-1 was increased on M1-polarized bone marrow derived macrophage. In necrotic cell-induced peritonitis model, ENO-1 blockade could ameliorate the migration of monocytes and neutrophils. Moreover, treatment with anti-ENO-1 antibody could attenuate bleomycin (BLM) and lipopolysaccharide (LPS)-induced acute lung injury (ALI) and inflammation, with a reduced pulmonary influx of neutrophils and monocytes, as well as lower levels of MCP-1, IL-1β, TNFα, IL-6 and KC in the bronchoalveolar lavage fluid (BALF). In LPS-induced ALI, anti-ENO-1 antibody treatment also reduced the accumulation of protein and DNA (indicator of neutrophil extracellular traps) in BALF. Taken together, these data indicate that targeting ENO-1 using anti-ENO-1 antibodies may serve as a potential treatment for ALI/acute respiratory distress syndrome (ARDS).