Extracellular vesicles and lupus nephritis - New insights into pathophysiology and clinical implications

Abstract

Lupus nephritis (LN) is a major cause for overall morbidity and mortality in patients with systemic lupus erythematosus (SLE), while its pathogenic mechanisms are still not well understood. Extracellular vesicles (EVs) are membrane vesicles that are released from almost all cell types. EVs can be subdivided into exosomes, microvesicles, and apoptotic bodies. Latest studies have shown that EVs can be released during several cellular events, including cell activation, autophagy, and several types of programed cell death, i.e. apoptosis, necroptosis, pyroptosis, and NETosis. Emerging evidence demonstrates that EVs harbor different bioactive molecules, including nucleic acids, proteins, lipids, cytokines, immune complexes (ICs), complements, and other molecules, some of which may contribute to pathogenesis of autoimmune diseases. EVs can serve as novel information shuttle to mediate local autocrine or paracrine signals to nearby cells, and distant endocrine signals to cells located far away. In LN, EVs may have pathogenic effects by transportation of autoantigens or complements, promotion of IC deposition or complement activation, and stimulation of inflammatory responses, renal tissue injury, or microthrombus formation. Additionally, EVs released from kidney cells may serve as specific biomarkers for diagnosis or monitoring of disease activity and therapeutic efficacy. In this review, we will summarize the latest progress about EV generation from basic research, their potential pathologic effects on LN, and their clinical implications. The cutting-edge knowledge about EV research provides insights into novel therapeutic strategy, new tools for diagnosis or prognosis, and evaluation approaches for treatment effectiveness in LN.

Keywords: Autoantigen; Extracellular vesicles; Immune complex; Inflammation; Lupus nephritis.

Conflict of interest statement

Competing interests Authors have declared that no conflict interests exist.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Fig. 1.. Schematic illustration of mechanistic generation of exosomes from different cellular events

Brief mechanisms for exosome generation in autophagy [41, 42], and apoptotic [26] cells (upper portion). Molecular and cellular mechanisms that regulate exosome biogenesis and/or release. The process can be divided into three steps: exosome biogenesis, transportation of MVBs to the plasma membrane, and fusion of MVBs with plasma membrane. [–163] (lower portion).

Fig. 2.. Schematic illustration of mechanistic generation of MVs from different cellular events

Brief mechanisms of MV generation from pyroptotic [27, 29, 34], necroptotic [30, 38], apoptotic [25], and NETotic [39, 164] cells (upper portion). Molecular and cellular mechanisms that regulate MVs biogenesis and/or release. The process can be divided into three steps. First, membrane-, cytoplasmic- and nuclear- associated cargoes are clustered in specific membrane microdomains of the plasma membrane. Second, the clustered cargoes together with additional machineries promote actin/cytoskeletal rearrangement, phosphatidylserine (PS) exposure, and membrane budding. Then a fission process at the plasma membrane occur. Besides, ARF6 can mediate the secretion of recycling endosome to form MVs. [–169] (lower portion).

Fig. 3.. Potential pathogenic effects of EVs on Lupus Nephritis.

A. EVs: as the source of autoantigens: EVs that are released from activated/dead/dying cells may carry autoantigens, particularly those from nucleus or cytoplasm. B. Deposition of EV-ICs: EVs harbor immunoglobulins and complement, thereby forming EVs containing immune complexes (EV-ICs). These EV-ICs along with immune-active structures and molecules deposit in kidney. EVs molecules, including G3BP, histone, fibronectin, may facilitate glomerular IC deposition. C. EVs carry and activate complements: EVs may carry many complement molecules, like C3, MAC, complement regulators. On the other hand, EVs may activate complement system through either classical or alternative pathways. Some EVs may activate the classical pathway through binding C1q, while other EVs, i.e. PS containing EVs, may also be activator of complements through the alternative pathway. D. Renal tissue damage: EV-associated activated complements and the consequent pro-inflammatory microenvironment causes podocyte injury, foot process effacement, and proliferation of mesangial cells, plus MPO-mediated endothelial damage, therefore leading to proteinuria and glomerular dysfunction. E. Pro-inflammation: EVs may carry pro-inflammatory components (cytokines, inflammasome, adhesion molecules, leukotriene, etc.), which further propagate inflammatory responses by activation of other immune cells. In addition, EVs and EV-ICs may activate complement system. F. Microthrombosis: PS- and TF-positive EVs as well as the EVs associated with complements are procoagulant, thus contributing to microthrombosis in lupus nephritis.