Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps.
Constitutively active neutrophil extracellular traps (NETs) and elevated plasma homocysteine are independent risk factors for Type 2 Diabetes (T2D) associated vascular diseases. Here, we show robust NETosis due to elevated plasma homocysteine levels in T2D subjects and increased components of NETs such as neutrophil elastase and cell free DNA. Cooperative NETs formation was observed in neutrophils exposed to homocysteine, IL-6 and high glucose suggesting acute temporal changes tightly regulate constitutive NETosis. Homocysteine induced NETs by NADPH oxidase dependent and independent mechanisms. Constitutively higher levels of calcium and mitochondrial superoxides under hyperglycemic conditions were further elevated in response to homocysteine leading to accelerated NETosis. Homocysteine showed robust interaction between neutrophils and platelets by inducing platelet aggregation and NETosis in an interdependent manner. Our data demonstrates that homocysteine can alter innate immune function by promoting NETs formation and disturbs homeostasis between platelets and neutrophils which may lead to T2D associated vascular diseases.
School of Life Sciences, Manipal University, Manipal, India.
Manjunath B
MB
Joshi
School of Life Sciences, Manipal University, Manipal, India.
Guruprasad
G
Baipadithaya
School of Life Sciences, Manipal University, Manipal, India.
Aswath
A
Balakrishnan
School of Life Sciences, Manipal University, Manipal, India.
Mangala
M
Hegde
School of Life Sciences, Manipal University, Manipal, India.
Manik
M
Vohra
School of Life Sciences, Manipal University, Manipal, India.
Rayees
R
Ahamed
Department of Medicine, Kasturba Medical College, Manipal University, Manipal, India.
Shivashankara K
SK
Nagri
Department of Surgery, Kasturba Medical College, Manipal University, Manipal, India.
Lingadakai
L
Ramachandra
School of Life Sciences, Manipal University, Manipal, India.
Kapaettu
K
Satyamoorthy
D001792:Blood Platelets / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000073888:Cell-Free Nucleic Acids / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D065206:Extracellular Traps / Q000378:metabolism*; D005260:Female; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D015854:Up-Regulation
D000073888:Cell-Free Nucleic Acids; D006710:Homocysteine; D019255:NADPH Oxidases; D019272:Leukocyte Elastase; D002118:Calcium