The hypercitrullination that we observed during NETosis in primar

The hypercitrullination that we observed during NETosis in primary human PMNs and EPRO cells sti mulated with diverse stimuli confirms an earlier report of citrullination in HL 60 cell derived NETs. Con sistent with this finding, scientific assay we observed a corresponding decrease in arginine methylation during NETosis of human and mouse neutrophils, likely reflecting conver sion of arginine residues to citrulline. Other, more subtle differences were observed in multiple marks across different conditions, however, given the ECL amplification approach used in most standard immuno blotting approaches, along with the performance of most commercial Inhibitors,Modulators,Libraries polyclonal antibodies, it is difficult to ascertain whether such differences are biologically significant.

However, many but not all PTMs that were recog nized by serum autoantibodies from Inhibitors,Modulators,Libraries SLE patients were found in NETs. Many of the serum reactive PTMs found in NETs were detected at only modest levels in both SLE histone positive and healthy serum samples, for both IgG and IgM isotypes. Surprisingly, histone PTMs toward which significantly more reactivity was observed in sera from SLE patients known to have anti histone antibodies, were absent or detected at only low levels in NETs produced from HL 60 or EPRO cells. To account for this discordance, one possibility may be that acetylated histones are dissociated during the chromatin condensation step in NETosis acetylated his tones are thought to be in a looser conformation within the nucleosome due to loss of positive charge on acetyl lysine residues.

It is also conceivable Inhibitors,Modulators,Libraries that these acetyl histones may be particularly immunogenic since they may disperse more widely, increasing their chances of uptake by a professional antigen presenting cell, gen erating a subsequent proinflammatory response by the adaptive immune system. A second possibility is that only the NETs from a special subpopulation of polymor phonuclear cells are responsible for their immunogeni city in SLE. A recent study Inhibitors,Modulators,Libraries described the discovery of low density granulocytes whose greater tendency to undergo NETosis elicited a stronger immune response than conventional neutrophils. Numerous studies have investigated the significance of histone acetylation in SLE, and the pattern of evidence suggests that histone acetylation within cells negatively correlates with disease activity.

Splenocytes from MRL lpr mice have hypoacetylated histones Inhibitors,Modulators,Libraries H3 and H4 when compared to control MRL MPJ mice and adminis tration of trichostatin A inhibitor to MRL lpr mice can be used to improve dis ease outcome. In T cells isolated from SLE patients, global H3 and H4 hypoacetylation was observed when compared to cells obtained from healthy donors. Furthermore, mice with a conditional knock in of the p300 acetyltransferase gene develop spontaneous lupus like disease.

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