a) TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP
Janin Knop, Lisanne M. Spilgies, Stefanie Rufli, Ramona Reinhart, Lazaros Vasilikos, Monica Yabal, Erika Crowley, Philipp J. Jost, Rebecca A. Marsh, Harald Wajant, Mark D. Robinson, Thomas Kaufmann & W. Wei-Lynn Wong.
Cell Death & Disease 10(10), 700. https://www.nature.com/articles/s41419-019-1938-x
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.
b) Tumor cell-derived lymphotoxin alpha triggers metastastic extravasation through TNFRs/cIAP1
Lazaros Vasilikos, Kay Hänggi, Lisanne M. Spilgies, W. Wei-Lynn Wong
BioRxiv 2019 https://doi.org/10.1101/766485
Metastasis involves the interaction of the tumor, immune and endothelial cells. Cell death proteins, such as inhibitors of apoptosis proteins (IAPs), are critical players in survival, inflammation and permeability. Whether the use of Smac mimetics, which target cIAP1/2 for degradation would affect metastasis is unknown. We show Smac mimetics reduced metastasis due to the loss of cIAP1 but not cIAP2 in experimental metastasis models. The endothelial compartment rather than the immune cells was responsible for reduction of extravasation upon loss of cIAP1. Loss of cIAP1 in primary endothelial cells did not lead to cell death but resulted in an unresponsive endothelium barrier to permeability factors causing a reduction in tumor cell extravasation. Unexpectedly, the co-loss of TNFR1 and cIAP1 restored the tumor load. We were surprised to find lymphotoxin alpha (LTA), and not TNF, secreted by the tumor cells was critical for the extravasation. Using TCGA data, we found high levels of LTA mRNA expression correlated with decreased survival in kidney carcinoma and associated with advance disease stage. Our data suggest that Smac mimetics, targeting cIAP1/2, may reduce metastasis to the lung through a LTA/TNFR mechanism by altering the endothelial barrier and inhibiting the ability of tumor cells to extravasate.