Staphylococcus aureus-Derived alpha-Hemolysin Evokes Generation of Specialized Pro-resolving Mediators Promoting Inflammation Resolution
CELL REPORTS
Authors: Jordan, Paul M.; Gerstmeier, Jana; Pace, Simona; Bilancia, Rossella; Rao, Zhigang; Boerner, Friedemann; Miek, Laura; Gutierrez-Gutierrez, Oscar; Arakandy, Vandana; Rossi, Antonietta; Ialenti, Armando; Gonzalez-Estevez, Cristina; Loeffler, Bettina; Tuchscherr, Lorena; Serhan, Charles N.; Werz, Oliver
Abstract
Underlying mechanisms of how infectious inflammation is resolved by the host are incompletely understood. One hallmark of inflammation resolution is the activation of specialized pro-resolving mediators (SPMs) that enhance bacterial clearance and promote tissue repair. Here, we reveal alpha-hemolysin (Hla) from Staphylococcus aureus as a potent elicitor of SPMbiosynthesis in human M2-likemacrophages and in the mouse peritoneum through selective activation of host 15-lipoxygenase-1 (15-LOX-1). S. aureus-induced SPMformation in M2 is abolished upon Hla depletion or 15-LOX-1 knockdown. Isolated Hla elicits SPM formation in M2 that is reverted by inhibition of the Hla receptor ADAM10. Lipid mediators derived from Hla-treated M2 accelerate planarian tissue regeneration. Hla but not zymosan provokes substantial SPM formation in the mouse peritoneum, devoid of leukocyte infiltration and pro-inflammatory cytokine secretion. Besides harming the host, Hla may also exert beneficial functions by stimulating SPM production to promote the resolution of infectious inflammation.
Degradome of soluble ADAM10 and ADAM17 metalloproteases
CELLULAR AND MOLECULAR LIFE SCIENCES
Authors: Scharfenberg, Franka; Helbig, Andreas; Sammel, Martin; Benzel, Julia; Schlomann, Uwe; Peters, Florian; Wichert, Rielana; Bettendorff, Maximilian; Schmidt-Arras, Dirk; Rose-John, Stefan; Moali, Catherine; Lichtenthaler, Stefan F.; Pietrzik, Claus U.; Bartsch, Joerg W.; Tholey, Andreas; Becker-Pauly, Christoph
Abstract
Disintegrin and metalloproteinases (ADAMs) 10 and 17 can release the extracellular part of a variety of membrane-bound proteins via ectodomain shedding important for many biological functions. So far, substrate identification focused exclusively on membrane-anchored ADAM10 and ADAM17. However, besides known shedding of ADAM10, we identified ADAM8 as a protease capable of releasing the ADAM17 ectodomain. Therefore, we investigated whether the soluble ectodomains of ADAM10/17 (sADAM10/17) exhibit an altered substrate spectrum compared to their membrane-bound counterparts. A mass spectrometry-based N-terminomics approach identified 134 protein cleavage events in total and 45 common substrates for sADAM10/17 within the secretome of murine cardiomyocytes. Analysis of these cleavage sites confirmed previously identified amino acid preferences. Further in vitro studies verified fibronectin, cystatin C, sN-cadherin, PCPE-1 as well as sAPP as direct substrates of sADAM10 and/or sADAM17. Overall, we present the first degradome study for sADAM10/17, thereby introducing a new mode of proteolytic activity within the protease web.
COA
Certificate of Analysis
