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Neutrophils cause a “NET” increase in skin allograft allogenicity

Abstract : While current immunosuppressive treatments efficiently prevent early rejection of organ transplants such as kidney, they have little or no effect in skin transplantation.Initial trauma and tissue injury resulting from the application of a skin allograft to a wound is associated with a potent inflammatory process and the initiation of both an innate and an adaptive immune response. The current study of Wong et al1 reveals the importance of neutrophils and neutrophil extracellular traps (NETs) in skin al-lograft rejection both in a mouse model and in allografts from pa-tients with burns.NETs are large, extracellular structures composed of a mixture of cytosolic and granule proteins assembled on a platform of de-condensed chromatin. Formation of NET requires the activation of peptidylarginine deiminase 4 (PAD4) that citrullinates arginine residues on histones leading to chromatin decondensation before NET release (reviewed in 2). The mechanism of NET clearance is not entirely understood, although activation of the plasma nuclease DNAse1 rapidly degrades NET-associated DNA.3The current report reveals that cleavage of ultralarge von Willebrand Factor (vWF) in recipients, by a vWF specific recombi-nant protease (ADAMTS13), increased skin allograft survival across a full MHC mismatch in mice. Neutrophils were recruited and NETs were bound by vWF, and ADAMTS13 treatment both reduced the number of neutrophils and abrogated NETs in allografts. In PAD4-deficient mice, ADAMTS13 treatment did not further improve al-lograft survival, leading to the suggestion that both were targeting the same pathway. Studies in tissue from patients with severe burns reiterated the observation of enrichment of neutrophils and NETs in skin allografts.The authors suggest that preventing the formation of NETs could be a useful strategy to prolong skin allograft survival and that tar-geting the PAD4 pathway could also be helpful. They point out that PAD4 inhibition would potentially have other beneficial anti-inflam-matory effects by reducing pro-inflammatory cytokine production.Although the mechanism of ADAMTS13 reduction of neutrophils and NETs in skin allografts was not elucidated, it was proposed to depend on destruction of the site of neutrophil recruitment and NET adhesion within the graft. The pathway to NET potentiation of the alloimmune response remains unclear, although NET-mediated acti-vation of intragraft antigen-presenting cells (eg, Langerhans cells or endothelial cells) may be envisaged. Previous studies have reported histone-mediated endothelial cell activation, and a link between NETs and endothelial damage has been proposed in an autoimmune vasculitis.4 The cytotoxicity of NETs for endothelial cells has also been reported, and this may potentiate intragraft inflammation.The importance of this article is not only due to the observation that large aggregates of DNA or NETS contribute to the alloimmune re-sponse but also due to the identification of new and plausible therapeu-tic targets to prevent allogenic skin-graft rejection. This would represent a major advance in the practice of skin grafts in nonoptimal conditions, particularly in situations where the possibility of carrying out an autolo-gous skin graft is unavailable. It is unfortunately the case that many such situations arise outside specialized skin transplantation centers.Finally, a recent study of metoprolol, a selective β1-adrenergic receptor antagonist, reported the ability of this drug to directly in-hibit the capacity of neutrophils to infiltrate tissues in vivo in a model of peritonitis.5 This, too, could be considered as a future means of denying NETs access to the allograft.
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https://www.hal.inserm.fr/inserm-02448967
Contributor : Sylvie Le Bihan <>
Submitted on : Wednesday, January 22, 2020 - 3:47:15 PM
Last modification on : Saturday, February 15, 2020 - 1:27:57 AM

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Sophie Brouard, Nuala Mooney. Neutrophils cause a “NET” increase in skin allograft allogenicity. American Journal of Transplantation, Wiley, 2019, ⟨10.1111/ajt.15746⟩. ⟨inserm-02448967⟩

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