Deimination and expression of peptidylarginine deiminases during cutaneous wound healing in mice

Coudane, Fanny; Méchin, Marie-Claire; Huchenq, A.; Henry, Julie; Nachat, Rachida; Ishigami, Akihito; Adoue, Véronique; Sebbag, Mireille; Serre, Guy; Simon, Michel

doi:10.1684/ejd.2011.1394

Cited by 25 publications

(18 citation statements)

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“…Furthermore, we reported that PAD4 deiminated MBP, as well as PAD2 in vitro (Wood et al, 2008). In a recent report, Coudane et al showed that the presence of citrullinated proteins in the PAD2 knockout mouse was independent of the presence or absence of PAD2 (Coudane et al, 2011). Therefore, citrullination was active in the PAD2 knockout, suggesting that ablation of citrullination requires knockout of all PAD activity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis

Moscarello

Lei

Mastronardi

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYMultiple sclerosis (MS) is the most common CNS-demyelinating disease of humans, showing clinical and pathological heterogeneity and a general resistance to therapy. We first discovered that abnormal myelin hypercitrullination, even in normal-appearing white matter, by peptidylarginine deiminases (PADs) correlates strongly with disease severity and might have an important role in MS progression. Hypercitrullination is known to promote focal demyelination through reduced myelin compaction. Here we report that 2-chloroacetamidine (2CA), a small-molecule, PAD active-site inhibitor, dramatically attenuates disease at any stage in independent neurodegenerative as well as autoimmune MS mouse models. 2CA reduced PAD activity and protein citrullination to pre-disease status. In the autoimmune models, disease induction uniformly induced spontaneous hypercitrullination with citrulline+ epitopes targeted frequently. 2CA rapidly suppressed T cell autoreactivity, clearing brain and spinal cord infiltrates, through selective removal of newly activated T cells. 2CA essentially prevented disease when administered before disease onset or before autoimmune induction, making hypercitrullination, and specifically PAD enzymes, a therapeutic target in MS models and thus possibly in MS.

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Section: Discussionmentioning

confidence: 99%

Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis

Moscarello

Lei

Mastronardi

et al. 2013

Disease Models &Amp; Mechanisms

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“…Perhaps the best demonstration that PAD-mediated citrullination can facilitate nonautoimmune or microbial-induced inflammatory events is the recent finding that PAD activity is strongly upregulated in inflamed tissue following a sterile skin punch biopsy procedure in mice [79]. Thus, it can be inferred that PAD-mediated citrullination plays a critical and fundamental role in inflammatory events induced by a range of pathologies, both infectious and noninfectious.…”

Section: Pad-mediated Citrullination: Linking Inflammation With Camentioning

confidence: 99%

Potential Role of Peptidylarginine Deiminase Enzymes and Protein Citrullination in Cancer Pathogenesis

Mohanan

Cherrington

Horibata

et al. 2012

Biochemistry Research International

108

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The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein-bound arginine and methylarginine residues to the uncharged, nonstandard amino acid citrulline. This enzymatic activity is referred to as citrullination or, alternatively, deimination. Citrullination can significantly affect biochemical pathways by altering the structure and function of target proteins. Five mammalian PAD family members (PADs 1–4 and 6) have been described and show tissue-specific distribution. Recent reviews on PADs have focused on their role in autoimmune diseases. Here, we will discuss the potential role of PADs in tumor progression and tumor-associated inflammation. In the context of cancer, increasing clinical evidence suggests that PAD4 (and possibly PAD2) has important roles in tumor progression. The link between PADs and cancer is strengthened by recent findings showing that treatment of cell lines and mice with PAD inhibitors significantly suppresses tumor growth and, interestingly, inflammatory symptoms. At the molecular level, transcription factors, coregulators, and histones are functional targets for citrullination by PADs, and citrullination of these targets can affect gene expression in multiple tumor cell lines. Next generation isozyme-specific PAD inhibitors may have therapeutic potential to regulate both the inflammatory tumor microenvironment and tumor cell growth.

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“…11), our data demonstrate that PAD4, the only nuclear PAD, is essential for the histone H3 citrullination and NETosis in skin wounds. Coudane et al 28 reported that PAD4 is the main PAD isoform detected in scabs of wounds from WT mice, and that PAD2 is unnecessary for citrullination of scab proteins as observed in PAD2-deficient mice, further strengthening the unique deimination role of PAD4 in the wounds.…”

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confidence: 94%

Diabetes primes neutrophils to undergo NETosis, which impairs wound healing

Wong

Demers

Martinod

et al. 2015

Nat Med

896

858

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Wound healing is impaired in diabetes resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins1. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed, NETosis). Expression of peptidylarginine deiminase 4 (PAD4), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4−/− mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds and healing was delayed. Wound healing was accelerated in Padi4−/− mice as compared to WT mice, and was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes where neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.

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Deimination and expression of peptidylarginine deiminases during cutaneous wound healing in mice

Cited by 25 publications

References 0 publications

Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis

Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis

Potential Role of Peptidylarginine Deiminase Enzymes and Protein Citrullination in Cancer Pathogenesis

Diabetes primes neutrophils to undergo NETosis, which impairs wound healing

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