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RIPK3-MLKL – Mediated neutrophil death requires concurrent activation of fibroblast activation protein alpha (FAP-α)

Wang, Xiaoliang, Perozzo, Remo, Amirshahrokhi, Keyvan, Kuchen, Stefan, Yousefi, Shida, Simon, Hans-Uwe, Loetscher, Pius and Gessier, Francois (2020) RIPK3-MLKL – Mediated neutrophil death requires concurrent activation of fibroblast activation protein alpha (FAP-α). The Journal of Immunology. ISSN 0022-17671550-6606


Cytokine-primed neutrophils can undergo a non-apoptotic type of cell death using components of the necroptotic pathway, including receptor-interacting protein kinase-3 (RIPK3), mixed lineage kinase-like (MLKL) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In this report, we provide evidence for a potential role of serine proteases in CD44-mediated necroptotic death of GM-CSF-primed human neutrophils. N-p-Tosyl-L-phenylalanine chloromethyl ketone (TPCK), a general serine protease inhibitor, completely blocked both cell death and CD44-mediated production of reactive oxidative species (ROS), suggesting that at least one serine protease is active in the death pathway proximal to NADPH oxidase activation. In subsequent experiments, we observed that several inhibitors known to block the enzymatic function of FAP-α were also able to block CD44-mediated ROS production and cell death, but not FAS receptor – mediated apoptosis. To understand how FAP-α is involved in this non-apoptotic death pathway, we performed immunoblotting experiments in the presence and absence of inhibitors of RIPK3, MLKL, p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3’-kinase (PI3K) and FAP-α. The results of these experiments suggested that FAP-α is active in parallel with RIPK3, MLKL and p38 MAPK activation, but proximal to PI3K and NADPH oxidase activation. Interestingly, neutrophils isolated from the joints of patients suffering from rheumatoid arthritis (RA) underwent a GM-CSF - independent necroptosis following CD44 ligation; this effect was also blocked by both FAP-α and MLKL inhibitors. Taken together, our evidence shows that the RIPK3 – MLKL pathway activates NADPH oxidase, but requires, in addition to p38 MAPK and PI3K, a serine protease activity, whereby FAP-α is the most likely candidate. Thus, FAP-α could be a potential drug target in neutrophilic inflammatory responses to avoid exaggerated non-apoptotic neutrophil death leading to tissue damage.

Item Type: Article
Date Deposited: 12 Sep 2020 00:45
Last Modified: 12 Sep 2020 00:45


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