Sera from patients with type 2 diabetes and neuropathy induce autophagy and colocalization with mitochondria in SY5Y cells.
The etiology of diabetic neuropathy is multifactorial and not fully elucidated, although oxidative stress and mitochondrial dysfunction are major factors. We reported previously that complement-inactivated sera from type 2 diabetic patients with neuropathy induce apoptosis in cultured neuronal cells, possibly through an autoimmune immunoglobulin-mediated pathway. Recent evidence supports an emerging role for autophagy in a variety of diseases. Here we report that exposure of human neuroblastoma SH-SY5Y cells to sera from type 2 diabetic patients with neuropathy is associated with increased levels of autophagosomes that is likely mediated by increased titers of IgM or IgG autoimmune immunoglobulins. The increased presence of macroautophagic vesicles was monitored using a specific immunohistochemical marker for autophagosomes, anti-LC3-II immunoreactivity, as well as the immunohistochemical signal for beclin-1, and was associated with increased co-localization with mitochondria in the cells exposed to diabetic neuropathic sera. We also report that dorsal root ganglia removed from streptozotocin-induced diabetic rats exhibit increased levels of autophagosomes and co-localization with mitochondria in neuronal soma, concurrent with enhanced binding of IgG and IgM autoimmune immunoglobulins. To our knowledge, this is the first evidence that the presence of autophagosomes is increased by a serum factor, likely autoantibody(ies) in a pathological condition. Stimulation of autophagy by an autoantibody-mediated pathway can provide a critical link between the immune system and the loss of function and eventual demise of neuronal tissue in type 2 diabetes.
Towns
Roberto
R
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0108, USA.
Kabeya
Yukiko
Y
Yoshimori
Tamotsu
T
Guo
Chunfang
C
Shangguan
Yu
Y
Hong
Shuangsong
S
Kaplan
Mariana
M
Klionsky
Daniel J
DJ
Wiley
John W
JW
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015551:Autoimmunity; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology*; D003929:Diabetic Neuropathies / Q000097:blood / Q000276:immunology*; D005260:Female; D005727:Ganglia, Spinal / Q000473:pathology; D006801:Humans; D007106:Immune Sera / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D007106:Immune Sera; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins