Renal Division, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
Neuroscience Section, Dino Ferrari Centre, Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy.
Autoimmun Rev. 2022 Aug;21(8):103132. doi: 10.1016/j.autrev.2022.103132. Epub 2022 Jun 9.
Autophagy is a highly regulated process wherein an unwanted cargo of damaged and dysfunctional cytoplasmic components is removed, delivered to lysosomes for degradation, and released back into the cytoplasm. Accumulating evidence suggests an important role of autophagy in the pathophysiology of systemic lupus erythematosus, with profound effects on both innate and adaptive immunity. Autophagy downregulation results in the inhibition of antigen presenting cells, reduced release of neutrophil extracellular traps and decreased activation of effector T and B cells, leading to reduced autoantibody production and attenuated type 1 interferon signaling. However, defective autophagy may accelerate the production of other inflammatory cytokines and reduce the clearance of apoptotic cells, promoting lupus development. In addition, autophagy dysfunction can concur to the pathogenesis of kidney injury in lupus nephritis. Autophagy is a pivotal mechanism to maintain podocyte integrity and endothelial cell survival. Several animal models have demonstrated that defective autophagy leads to podocyte injury and can promote an endothelial pro-inflammatory and atherogenic phenotype. Moreover, autophagy is a key homeostatic regulator of renal tubular cells, and recent evidence has pointed out that chronic autophagy deficiency may accelerate kidney fibrosis. Targeting autophagy may theoretically improve lupus nephritis outcomes, but novel, non-invasive methods to measure and monitor autophagic activity are urgently needed. In addition, the extent and timing of autophagy inhibition still require additional studies before clinical translation may be attempted. In this review, we will also discuss the effect of several clinically available drugs that can regulate the autophagic flux and their effect in lupus nephritis patients.
自噬是一个高度调控的过程，其中受损和功能失调的细胞质成分被去除，递送至溶酶体进行降解，并重新释放回细胞质中。越来越多的证据表明自噬在系统性红斑狼疮的病理生理学中起着重要作用，对固有免疫和适应性免疫都有深远的影响。自噬下调导致抗原呈递细胞的抑制，减少中性粒细胞胞外陷阱的释放和效应 T 和 B 细胞的活化减少，导致自身抗体产生减少和 1 型干扰素信号减弱。然而，自噬缺陷可能会加速其他炎症细胞因子的产生，并减少凋亡细胞的清除，从而促进狼疮的发展。此外，自噬功能障碍可能会导致狼疮肾炎中的肾脏损伤。自噬是维持足细胞完整性和内皮细胞存活的关键机制。几个动物模型表明，自噬缺陷会导致足细胞损伤，并可能促进内皮炎症和动脉粥样硬化表型。此外，自噬是肾小管细胞的关键稳态调节剂，最近的证据表明，慢性自噬缺乏可能加速肾脏纤维化。靶向自噬理论上可以改善狼疮肾炎的预后，但需要新的、非侵入性的方法来测量和监测自噬活性。此外，自噬抑制的程度和时间仍需要进一步研究，然后才能尝试临床转化。在这篇综述中，我们还将讨论几种可调节自噬流的临床可用药物的作用及其在狼疮肾炎患者中的作用。
