P2Y12 antagonism results in altered interactions between platelets and regulatory T cells during sepsis,Journal of Leukocyte Biology

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P2Y12 antagonism results in altered interactions between platelets and regulatory T cells during sepsis
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2020-11-26 , DOI: 10.1002/jlb.3a0220-097r
Samara Albayati ₁ , Harika Vemulapalli ₁ , Alexander Y Tsygankov _{1,

2} , Elisabetta Liverani ₁

Affiliation

Sepsis is a complex clinical condition resulting from a serious bloodstream infection. With mortality rates as high as 50%, improved treatments are needed. Regulatory T cells (Tregs), a subset of T lymphocytes, promote the resolution of inflammation. Septic patients have elevated levels of circulating Tregs. Platelets influence the proliferation and activation of Tregs in vitro. However, modulating platelet-Tregs interaction during sepsis may restraing Treg proliferation, leading to the restoration of immunologic homeostasis. P2Y₁₂ is a purinergic receptor present on platelets and T lymphocytes. Blocking P2Y₁₂ improves the outcome of sepsis. We investigated whether blocking P2Y₁₂ alters platelet–Treg interaction in vivo. We used the murine model of sepsis, cecal ligation, and puncture (CLP) and we blocked P2Y₁₂ using the P2Y₁₂ antagonist, clopidogrel. Twenty-four hours after surgery, we measured Treg population sizes in the spleens of the Sham, CLP, and CLP + clopidogrel groups. We investigated the effect of blocking P2Y₁₂ in vitro using cocultures of human platelets and T cells with or without anti-CD3/CD28. P2Y₁₂ was blocked using AR-C69931MX. Treg population sizes were reduced in the septic mice treated with clopidogrel compared with untreated septic mice. Aggregation of platelets and CD4⁺ T cells was reduced in treated CLP mice compared with untreated CLP mice. P2Y₁₂ antagonism changes how platelets influence T cells in vitro, depending on T-cell activation. In conclusion, blockade of the P2Y₁₂ signaling pathway restrains Treg proliferation in vivo and in vitro. Targeting platelets to control Treg proliferation and activity may be a promising strategy for treating sepsis.

中文翻译：

P2Y12 拮抗作用导致败血症期间血小板和调节性 T 细胞之间的相互作用发生改变

脓毒症是一种由严重血流感染引起的复杂临床病症。由于死亡率高达 50%，因此需要改进治疗方法。调节性 T 细胞 (Tregs) 是 T 淋巴细胞的一个子集，可促进炎症的消退。脓毒症患者的循环 Treg 水平升高。血小板影响体外 Tregs 的增殖和活化。然而，在脓毒症期间调节血小板-Treg 相互作用可能会抑制 Treg 增殖，导致免疫稳态的恢复。P2Y ₁₂是一种存在于血小板和 T 淋巴细胞上的嘌呤能受体。阻断 P2Y ₁₂可改善败血症的结果。我们调查了是否阻断 P2Y ₁₂改变体内血小板-Treg相互作用。我们使用败血症、盲肠结扎和穿刺 (CLP) 的鼠模型，并使用 P2Y ₁₂拮抗剂氯吡格雷阻断 P2Y ₁₂。手术后 24 小时，我们测量了 Sham、CLP 和 CLP + 氯吡格雷组脾脏中 Treg 群体的大小。我们使用人血小板和 T 细胞的共培养物在有或没有抗 CD3/CD28 的情况下研究了体外阻断 P2Y ₁₂的效果。使用 AR-C69931MX 阻止了P2Y ₁₂。与未治疗的脓毒症小鼠相比，用氯吡格雷治疗的脓毒症小鼠的 Treg 种群大小减少。与未经处理的 CLP 小鼠相比，经处理的 CLP 小鼠的血小板和 CD4 ⁺ T 细胞的聚集减少。P2Y₁₂拮抗作用会改变血小板在体外影响 T 细胞的方式，这取决于 T 细胞的激活。总之，P2Y ₁₂信号通路的阻断抑制了体内和体外的 Treg 增殖。靶向血小板以控制 Treg 增殖和活性可能是治疗脓毒症的一种有前景的策略。

更新日期：2020-11-26

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