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An immunohistochemical atlas of necroptotic pathway expression.

ABSTRACT: Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase-8, RIPK1, RIPK3 and MLKL - in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

SUBMITTER: Chiou S

PROVIDER: S-EPMC11250867 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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An immunohistochemical atlas of necroptotic pathway expression.

Chiou Shene S Al-Ani Aysha H AH Pan Yi Y Patel Komal M KM Kong Isabella Y IY Whitehead Lachlan W LW Light Amanda A Young Samuel N SN Barrios Marilou M Sargeant Callum C Rajasekhar Pradeep P Zhu Leah L Hempel Anne A Lin Ann A Rickard James A JA Hall Cathrine C Gangatirkar Pradnya P Yip Raymond Kh RK Cawthorne Wayne W Jacobsen Annette V AV Horne Christopher R CR Martin Katherine R KR Ioannidis Lisa J LJ Hansen Diana S DS Day Jessica J Wicks Ian P IP Law Charity C Ritchie Matthew E ME Bowden Rory R Hildebrand Joanne M JM O'Reilly Lorraine A LA Silke John J Giulino-Roth Lisa L Tsui Ellen E Rogers Kelly L KL Hawkins Edwin D ED Christensen Britt B Murphy James M JM Samson André L AL

EMBO molecular medicine 20240515 7

Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase- ...[more]

PMID: 38750308

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Project description:Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of Cops8 (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin-proteasome system (UPS) but also the autophagic-lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1-RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.

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An immunohistochemical atlas of necroptotic pathway expression.

Publications

An immunohistochemical atlas of necroptotic pathway expression.

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