Cross-linking by tissue transglutaminase-2 alters fibrinogen-directed macrophage proinflammatory activity.
Cross-linking by tissue transglutaminase-2 alters fibrinogen-directed macrophage proinflammatory activity.
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DOI：
10.1111/jth.15670
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发表时间：
2022-05
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凝血因子纤维蛋白（原）可以通过改变白细胞活性来调节炎症。对纤维蛋白（原）介导的促炎活性的分析主要集中在通过凝血酶将纤维蛋白原转化为稳定的纤维蛋白聚合物所揭示的白细胞整联蛋白结合活性上。除凝血酶外，纤维蛋白原还是组织转氨酶-2（TG 2）的底物，TG 2是一种广泛表达的酶，可产生独特的纤维蛋白原Aα-γ链交联产物。我们测试了TG 2依赖性交联改变表面粘附纤维蛋白原的促炎活性的假设。将小鼠骨髓衍生的巨噬细胞（BMDM）在用纤维蛋白原或TG 2交联的纤维蛋白原（10 μg/mL）包被的组织培养板上培养，然后用脂多糖（LPS，1 ng/mL）或媒介物刺激不同的时间。在不存在LPS刺激的情况下，TG 2交联的纤维蛋白（原）增强炎性基因诱导（例如，TNFα）与未修饰的纤维蛋白原相比。LPS刺激诱导MAP激酶磷酸化、IκBα降解和促炎细胞因子（例如，TNFα）60分钟内。这种初始的细胞活化不受未修饰的或TG 2交联的纤维蛋白原的影响。相反，LPS诱导IL-10 mRNA和蛋白以及STAT 3磷酸化被TG 2交联的纤维蛋白原选择性地减弱，这与LPS刺激的BMDM在稍后的时间点（6和24小时）的促炎细胞因子分泌增强有关。结果表明，TG 2的非典型交联赋予表面粘附的纤维蛋白原独特的促炎活性。结果表明，一种新的非凝血依赖性机制控制纤维蛋白原导向的巨噬细胞活化。
The blood coagulation factor fibrin(ogen) can modulate inflammation by altering leukocyte activity. Analyses of fibrin(ogen)-mediated proinflammatory activity have largely focused on leukocyte integrin binding activity revealed by conversion of fibrinogen to a stabilized fibrin polymer by blood coagulation enzymes. In addition to coagulation enzymes, fibrinogen is a substrate for tissue transglutaminase-2 (TG2), a widely expressed enzyme that produces unique fibrinogen Aα-γ chain cross-linked products. We tested the hypothesis that TG2 dependent cross-linking alters the proinflammatory activity of surface-adhered fibrinogen. Mouse bone marrow-derived macrophages (BMDMs) were cultured on tissue culture plates coated with fibrinogen or TG2-cross-linked fibrinogen (10 μg/mL) and then stimulated with lipopolysaccharide (LPS, 1 ng/mL) or vehicle for various times. In the absence of LPS stimulation, TG2-cross-linked fibrin(ogen) enhanced inflammatory gene induction (e.g., Tnfα) compared with unmodified fibrinogen. LPS stimulation induced MAP kinase phosphorylation, IκBα degradation, and expression of proinflammatory cytokines (e.g., TNFα) within 60 minutes. This initial cellular activation was unaffected by unmodified or TG2-cross-linked fibrinogen. In contrast, LPS induction of IL-10 mRNA and protein and STAT3 phosphorylation was selectively attenuated by TG2-cross-linked fibrinogen, which was associated with enhanced proinflammatory cytokine secretion by LPS stimulated BMDMs at later time points (6 and 24 h). The results indicate that atypical cross-linking by TG2 imparts unique proinflammatory activity to surface-adhered fibrinogen. The results suggest a novel coagulation-independent mechanism controlling fibrinogen-directed macrophage activation.
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