The leukotriene B4 /BLT1-dependent neutrophil accumulation exacerbates immune complex-mediated glomerulonephritis.
The leukotriene B4 /BLT1-dependent neutrophil accumulation exacerbates immune complex-mediated glomerulonephritis.
复制标题
白三烯 B4 /BLT1 依赖性中性粒细胞积聚会加剧免疫复合物介导的肾小球肾炎。
DOI：
10.1096/fj.202201936r
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发表时间：
2023
期刊：
影响因子：
4.8
通讯作者：
Yokomizo T
中科院分区：
文献类型：
--
作者：
Shioda R;Jo-Watanabe A;Okuno T;Saeki K;Nakayama M;Suzuki Y;Yokomizo T
新月体形成是决定肾炎预后的最重要的病理发现。尽管已知中性粒细胞在新月体肾小球肾炎（如抗中性粒细胞胞质抗体（ANCA）相关性肾小球肾炎）的进展中起重要作用，但尚未确定ANCA相关性肾小球肾炎中中性粒细胞的关键化学引诱物。在这里，我们证明了一种脂质化学引诱物，白三烯B4（LTB 4），及其受体BLT 1主要参与免疫复合物介导的新月体肾小球肾炎小鼠模型的疾病发病机制。在发病后1 h内，循环中性粒细胞聚集到肾小球中，这伴随着LTB 4在肾皮质中的聚集，导致肾损伤。LTB 4通过中性粒细胞上Fc γ受体的交联产生。BLT 1或LTB 4生物合成缺陷的小鼠表现出抑制的初始中性粒细胞浸润和随后的血栓性肾小球肾炎和肾纤维化。中性粒细胞在疾病发作前而非之后的耗竭可防止蛋白尿和肾损伤，表明中性粒细胞在肾小球肾炎早期的重要作用。在疾病发作前后给予BLT 1拮抗剂几乎完全抑制了肾小球肾炎的诱导。最后，我们发现ANCA相关性肾小球肾炎患者的肾小球比其他病因患者的肾小球含有更多的BLT 1阳性细胞。总之，LTB 4-BLT 1轴是嗜中性肾小球炎症的关键驱动因素，并将成为新月体肾小球肾炎的新治疗靶点。
Crescent formation is the most important pathological finding that defines the prognosis of nephritis. Although neutrophils are known to play an important role in the progression of crescentic glomerulonephritis, such as anti‐neutrophil cytoplasmic antibody (ANCA)‐associated glomerulonephritis, the key chemoattractant for neutrophils in ANCA‐associated glomerulonephritis has not been identified. Here, we demonstrate that a lipid chemoattractant, leukotriene B4(LTB4), and its receptor BLT1 are primarily involved in disease pathogenesis in a mouse model of immune complex‐mediated crescentic glomerulonephritis. Circulating neutrophils accumulated into glomeruli within 1 h after disease onset, which was accompanied by LTB4accumulation in the kidney cortex, leading to kidney injury. LTB4was produced by cross‐linking of Fc gamma receptors on neutrophils. Mice deficient in BLT1 or LTB4biosynthesis exhibited suppressed initial neutrophil infiltration and subsequent thrombotic glomerulonephritis and renal fibrosis. Depletion of neutrophils before, but not after, disease onset prevented proteinuria and kidney injury, indicating the essential role of neutrophils in the early phase of glomerulonephritis. Administration of a BLT1 antagonist before and after disease onset almost completely suppressed induction of glomerulonephritis. Finally, we found that the glomeruli from patients with ANCA‐associated glomerulonephritis contained more BLT1‐positive cells than glomeruli from patients with other etiologies. Taken together, the LTB4‐BLT1 axis is the key driver of neutrophilic glomerular inflammation, and will be a novel therapeutic target for the crescentic glomerulonephritis.