Histone deimination as a response to inflammatory stimuli in neutrophils.
Posttranslational modifications, such as the deimination of arginine to citrulline by peptidyl arginine deiminase (PAD4), change protein structure and function. For autoantigens, covalent modifications represent a mechanism to sidestep tolerance and stimulate autoimmunity. To examine conditions leading to histone deimination in neutrophils, we used Abs that detect citrullines in the N terminus of histone H3. Deimination was investigated in human neutrophils and HL-60 cells differentiated into granulocytes. We observed rapid and robust H3 deimination in HL-60 cells exposed to LPS, TNF, lipoteichoic acid, f-MLP, or hydrogen peroxide, which are stimuli that activate neutrophils. Importantly, we also observed H3 deimination in human neutrophils exposed to these stimuli. Citrullinated histones were identified as components of extracellular chromatin traps (NETs) produced by degranulating neutrophils. In contrast, apoptosis proceeded without detectable H3 deimination in HL-60 cells exposed to staurosporine or camptothecin. We conclude that histone deimination in neutrophils is induced in response to inflammatory stimuli and not by treatments that induce apoptosis. Our results further suggest that deiminated histone H3, a covalently modified form of a prominent nuclear autoantigen, is released to the extracellular space as part of the neutrophil response to infections. The possible association of a modified autoantigen with microbial components could, in predisposed individuals, increase the risk of autoimmunity.
Neeli
Indira
I
Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Khan
Salar N
SN
Radic
Marko
M
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D002843:Chromatin / Q000378:metabolism; D002956:Citrulline / Q000032:analysis; D018922:HL-60 Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007097:Imines / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology*; D007476:Ionophores / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D014212:Tretinoin / Q000494:pharmacology
D002843:Chromatin; D006657:Histones; D007097:Imines; D007476:Ionophores; D002956:Citrulline; D014212:Tretinoin; D002118:Calcium