TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP.

Knop, Janin; Spilgies, Lisanne M; Rufli, Stefanie; Reinhart, Ramona; Vasilikos, Lazaros; Yabal, Monica; Crowley, Erika; Jost, Philipp J; Marsh, Rebecca A; Wajant, Harald; Robinson, Mark D; Kaufmann, Thomas; Wong, W Wei-Lynn (2019). TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP. Cell death & disease, 10(10), p. 700. Springer Nature 10.1038/s41419-019-1938-x

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The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap-/- macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap-/- myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Reinhart, Ramona and Kaufmann, Thomas

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2041-4889

Publisher:

Springer Nature

Language:

English

Submitter:

Sabrina Cookman

Date Deposited:

08 Oct 2019 15:03

Last Modified:

29 Jun 2020 16:01

Publisher DOI:

10.1038/s41419-019-1938-x

Related URLs:

PubMed ID:

31541082

BORIS DOI:

10.7892/boris.133710

URI:

https://boris.unibe.ch/id/eprint/133710

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