Extracellular Vesicle-Induced Classical Complement Activation Leads to Retinal Endothelial Cell Damage via MAC Deposition.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Complement Activation/*immunology ; Complement Membrane Attack Complex/*metabolism ; Endothelial Cells/*pathology ; Extracellular Vesicles/*metabolism ; Retina/*pathology; Animals ; Cell Death ; Cell Survival ; Complement C1/metabolism ; Diabetes Mellitus, Experimental/blood ; Diabetes Mellitus, Experimental/immunology ; Diabetes Mellitus, Experimental/pathology ; Extracellular Vesicles/ultrastructure ; Humans ; Immunoglobulins/metabolism ; Male ; Rats, Sprague-Dawley

Several studies have suggested that there is a link between membrane attack complex (MAC) deposition in the retina and the progression of diabetic retinopathy (DR). Our recent investigation demonstrated that circulating IgG-laden extracellular vesicles contribute to an increase in retinal vascular permeability in DR through activation of the complement system. However, the mechanism through which extracellular vesicle-induced complement activation contributes to retinal vascular cytolytic damage in DR is not well understood. In this study, we demonstrate that IgG-laden extracellular vesicles in rat plasma activate the classical complement pathway, and in vitro Streptozotocin (STZ)-induced rat diabetic plasma results in MAC deposition and cytolytic damage in human retinal endothelial cells (HRECs). Moreover, removal of the plasma extracellular vesicles reduced the MAC deposition and abrogated cytolytic damage seen in HRECs. Together, the results of this study demonstrate that complement activation by IgG-laden extracellular vesicles in plasma could lead to MAC deposition and contribute to endothelium damage and progression of DR.

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P30 DK020572 United States DK NIDDK NIH HHS; MICL02163 Michigan Experimental Agricultural Station; R01EY025383 United States NH NIH HHS; RO1EY016077 United States NH NIH HHS

Keywords: complement system; diabetic retinopathy; extracellular vesicles; human retinal endothelial cells (HRECs); membrane attack complex (MAC); retinal vascular damage

0 (Complement C1)
0 (Complement Membrane Attack Complex)
0 (Immunoglobulins)

Date Created: 20200304 Date Completed: 20201124 Latest Revision: 20201124

20240829

PMC7084203

10.3390/ijms21051693

32121610