Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation

Wang, Yanming; Li, Ming; Stadler, Sonja; Correll, Sarah; Li, Pingxin; Wang, Danchen; Hayama, Ryo; Leonelli, Lauriebeth; Han, Hee‐Sun; Grigoryev, Sergei A.; Allis, C. David; Coonrod, Scott A.

doi:10.1084/jem2062oia1

Cited by 246 publications

(369 citation statements)

References 1 publication

Supporting

Mentioning

347

Contrasting

Unclassified

Order By: Relevance

“…Prior to releasing NETs, neutrophil enzymes access the cell nucleus and promote chromatin decondensation [42] involving histone modifications. Histone citrullination is believed to be a hallmark of NET formation [49]. To identify signs of NET formation in the ischemic brain, we used an antibody against citrullinated histone 3 (Cit-H3).…”

Section: Comparative Regional Location Of Neutrophils Between the C-mmentioning

confidence: 99%

Neutrophil recruitment to the brain in mouse and human ischemic stroke

et al. 2014

View full text Add to dashboard Cite

Neutrophils are rapidly recruited in response to local tissue infection or inflammation. Stroke triggers a strong inflammatory reaction but the relevance of neutrophils in the ischemic brain is not fully understood, particularly in the absence of reperfusion. We investigated brain neutrophil recruitment in two murine models of permanent ischemia induced by either cauterization of the distal portion of the middle cerebral artery (c-MCAo) or intraluminal MCA occlusion (il-MCAo), and three fatal cases of human ischemic stroke. Flow cytometry analyses revealed progressive neutrophil recruitment after c-MCAo, lesser neutrophil recruitment following il-MCAo, and absence of neutrophils after sham operation. Confocal microscopy identified neutrophils in the leptomeninges from 6 h after the occlusion, in the cortical basal lamina and cortical Virchow-Robin spaces from 15 h, and also in the cortical brain parenchyma at 24 h. Neutrophils showed signs of activation including histone-3 citrullination, chromatin decondensation, and extracellular projection of DNA and histones suggestive of extracellular trap formation. Perivascular neutrophils were identified within the entire cortical infarction following c-MCAo. After il-MCAo, neutrophils prevailed in the margins but not the center of the cortical infarct, and were intraluminal and less abundant in the striatum. The lack of collaterals to the striatum and a collapsed pial anastomotic network due to brain edema in large hemispheric infarctions could impair neutrophil trafficking in this model. Neutrophil extravasation at the leptomeninges was also detected in the human tissue. We concluded that neutrophils extravasate from the leptomeningeal vessels and can eventually reach the brain in experimental animal models and humans with prolonged arterial occlusion.

show abstract

Section: Comparative Regional Location Of Neutrophils Between the C-mmentioning

confidence: 99%

Neutrophil recruitment to the brain in mouse and human ischemic stroke

et al. 2014

View full text Add to dashboard Cite

show abstract

“…PAD4 removes positive charges from core histones by converting arginine residues to citrullines, thereby weakening the interaction between histones and DNA. Inhibition of PAD4 was reported to decrease NET formation and PAD4-deficient mice to display impaired NETosis [3,4]. The neutrophil-specific serine proteases neutrophil elastase (NE) and myeloperoxidase (MPO) are involved in the later stages of NETosis.…”

Section: Introductionmentioning

confidence: 99%

How neutrophil extracellular traps orchestrate the local immune response in gout

et al. 2015

View full text Add to dashboard Cite

Neutrophil granulocytes possess a large arsenal of pro-inflammatory substances and mechanisms that empower them to drive local acute immune reactions to invading microorganisms or endogenous inflammatory triggers. The use of this armory needs to be tightly controlled to avoid chronic inflammation and collateral tissue damage. In gout, inflammation arises from precipitation of uric acid in the form of needle-shaped monosodium urate crystals. Inflammasome activation by these crystals in local immune cells results in a rapid and dramatic recruitment of neutrophils. This neutrophil influx is accompanied by the infamously intense clinical symptoms of inflammation during an acute gout attack. Neutrophilic inflammation however is equipped with a built-in safeguard; activated neutrophils form neutrophil extracellular traps (NETs). At the very high neutrophil densities that occur at the site of inflammation, NETs build aggregates that densely pack the monosodium urate (MSU) crystals and trap and degrade pro-inflammatory mediators by inherent proteases. Local removal of cytokines and chemokines by aggregated NETs explains how acute inflammation can stop in the consistent presence of the inflammatory trigger. Aggregated NETs resemble early stages of the typical large MSU deposits that constitute the pathognomonic structures of gout, tophi. Although tophi contribute to muscosceletal damage and mortality in patients with chronic gout, they can therefore be considered as a payoff that is necessary to silence the intense inflammatory response during acute gout.

show abstract

“…Peptidylarginine 178 deiminase 4 (PAD4) induced in the neutrophil after proper activation 179 catalyzes deimination of arginine residues that yields citrulline in three 180 out of the four core histones, which results in their weaker binding to 181 DNA. There is evidence that histones are citrullinated in decondensed 182 chromatin [27][28][29]. The role of this process in NETosis was demonstrated 183 pharmacologically for cell lines forming a limited number of NETs.…”

mentioning

confidence: 99%