Robin Schwarzer

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

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Manolis Pasparakis

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Laurens Wachsmuth

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Huipeng Jiao

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Snehlata Kumari

University of Queensland

Marcus Krüger

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Vangelis Kondylis

Heinrich Heine University Düsseldorf

Remzi Onur Eren

University of Cologne

Teresa Corona

Instituto Nacional de Neurología y Neurocirugía

William J. Kaiser

The University of Texas Health Science Center at San Antonio

Katerina Vlantis

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Cooperative Institutions

University of Cologne

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

University Hospital Cologne

Kiel University

University of Lübeck

University Hospital Schleswig-Holstein

Max Planck Institute for Metabolism Research

Harvard University

Max Planck Institute for Biology of Ageing

Universität Hamburg

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ZBP1 causes inflammation by inducing RIPK3-mediated necroptosis and RIPK1 kinase activity-independent apoptosis

Cell Death and Differentiation (2024)

Lioba Koerner Laurens Wachsmuth Snehlata Kumari Robin Schwarzer Theresa Wagner

Abstract Z-DNA binding protein 1 (ZBP1) has important functions in anti-viral immunity and in the regulation of inflammatory responses. ZBP1 induces necroptosis by directly engaging and activating RIPK3, however, the mechanisms by which ZBP1 induces inflammation and in particular the role of RIPK1 and the contribution of cell death-independent signaling remain elusive. Here we show that ZBP1 causes skin inflammation by inducing RIPK3-mediated necroptosis and RIPK1-caspase-8-mediated apoptosis in keratinocytes. ZBP1 induced TNFR1-independent skin inflammation in mice with epidermis-specific ablation of FADD by triggering keratinocyte necroptosis. Moreover, transgenic expression of C-terminally truncated constitutively active ZBP1 (ZBP1ca) in mouse epidermis caused skin inflammation that was only partially inhibited by abrogation of RIPK3-MLKL-dependent necroptosis and fully prevented by combined deficiency in MLKL and caspase-8. Importantly, ZBP1ca induced caspase-8-mediated skin inflammation by RHIM-dependent but kinase activity-independent RIPK1 signaling. Furthermore, ZBP1ca-induced inflammatory cytokine production in the skin was completely prevented by combined inhibition of apoptosis and necroptosis arguing against a cell death-independent pro-inflammatory function of ZBP1. Collectively, these results showed that ZBP1 induces inflammation by activating necroptosis and RIPK1 kinase activity-independent apoptosis.

RIPK1

FADD

10.1038/s41418-024-01321-6

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Citations (11)

IKKε and TBK1 prevent RIPK1 dependent and independent inflammation

Nature Communications (2024)

Remzi Onur Eren Göksu Gökberk Kaya Robin Schwarzer Manolis Pasparakis

Abstract TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poorly understood. Here we show that IKKε compensates for the loss of TBK1 kinase activity to prevent RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive versions of IKKε and TBK1 developed systemic inflammation that was induced by both RIPK1-dependent and -independent mechanisms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced RIPK1-dependent cell death and systemic inflammation mediated by IL-1 family cytokines. Tissue-specific studies showed that IKKε and TBK1 were required to prevent cell death and inflammation in the intestine but were dispensable for liver and skin homeostasis. Together, these findings revealed that IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflammation and maintain tissue homeostasis.

IκB kinase

TANK-binding kinase 1

RIPK1

10.1038/s41467-023-44372-y

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Citations (5)

NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-κB-Dependent and -Independent Functions

Immunity (2016)

Katerina Vlantis Andy Wullaert Apostolos Polykratis Vangelis Kondylis Marius Dannappel

Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.

RIPK1

Paneth cell

Intestinal epithelium

IκB kinase

RELB

FADD

10.1016/j.immuni.2016.02.020

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Citations (171)

New insights into the regulation of apoptosis, necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8

Current Opinion in Cell Biology (2020)

Robin Schwarzer Lucie Laurien Manolis Pasparakis

Pyroptosis

Caspase 8

10.1016/j.ceb.2020.02.004

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Citations (131)

Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation

Nature Communications (2020)

Lucie Laurien Masahiro Nagata Hannah Schünke Tom Delanghe Janica L. Wiederstein

Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.

10.1038/s41467-020-15466-8

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Citations (181)

Temporally Distinct Functions of the Cytokines IL-12 and IL-23 Drive Chronic Colon Inflammation in Response to Intestinal Barrier Impairment

Immunity (2019)

Christina Eftychi Robin Schwarzer Katerina Vlantis Laurens Wachsmuth Marijana Basic

Pathogenesis

Dysbiosis

Interleukin-23

Interleukin 22

10.1016/j.immuni.2019.06.008

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Citations (101)

ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS–STING

The Journal of Experimental Medicine (2018)

Konrad Aden Florian Tran Go Ito Raheleh Sheibani‐Tezerji Simone Lipinski

A coding variant of the inflammatory bowel disease (IBD) risk gene ATG16L1 has been associated with defective autophagy and deregulation of endoplasmic reticulum (ER) function. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. We show that ATG16L1 critically orchestrates IL-22 signaling in the intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress and subsequent activation of STING-dependent type I interferon (IFN-I) signaling, which is augmented in Atg16l1ΔIEC intestinal organoids. IFN-I signals amplify epithelial TNF production downstream of IL-22 and contribute to necroptotic cell death. In vivo, IL-22 treatment in Atg16l1ΔIEC and Atg16l1ΔIEC/Xbp1ΔIEC mice potentiates endogenous ileal inflammation and causes widespread necroptotic epithelial cell death. Therapeutic blockade of IFN-I signaling ameliorates IL-22–induced ileal inflammation in Atg16l1ΔIEC mice. Our data demonstrate an unexpected role of ATG16L1 in coordinating the outcome of IL-22 signaling in the intestinal epithelium.

ATG16L1

Intestinal epithelium

Intestinal mucosa

Proinflammatory cytokine

10.1084/jem.20171029

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Citations (143)

Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation

Nature (2020)

Huipeng Jiao Laurens Wachsmuth Snehlata Kumari Robin Schwarzer Juan Lin

RIPK1

10.1038/s41586-020-2129-8