title: Staphylococcal Superantigen-Like Protein 1 and 5 (SSL1 &amp; SSL5) Limit Neutrophil Chemotaxis and Migration through MMP-Inhibition.
abstract: Matrix metalloproteinases (MMPs) are endopeptidases that degrade components of the extracellular matrix, but also modulate inflammation. During bacterial infections, MMPs are important in the recruitment and migration of inflammatory cells. Besides facilitating cell migration by degrading extracellular matrix components, they potentiate the action of several inflammatory molecules, including cytokines, chemokines, and antimicrobial peptides. Staphylococcus aureus secretes an arsenal of immune evasion molecules that interfere with immune cell functioning and hamper proper immune responses. An earlier study identified staphylococcal superantigen-like protein 5 (SSL5) as an MMP9 inhibitor. Since multiple MMPs are involved in neutrophil recruitment, we set up an in-depth search for additional MMP inhibitors by testing a panel of over 70 secreted staphylococcal proteins on the inhibition of the two main neutrophil MMPs: MMP8 (neutrophil collagenase) and MMP9 (neutrophil gelatinase B). We identified SSL1 and SSL5 as potent inhibitors of both neutrophil MMPs and show that they are actually broad range MMP inhibitors. SSL1 and SSL5 prevent MMP-induced cleavage and potentiation of IL-8 and inhibit the migration of neutrophils through collagen. Thus, through MMP-inhibition, SSL1 and SSL5 interfere with neutrophil activation, chemotaxis, and migration, all vital neutrophil functions in bacterial clearance. Studies on MMP-SSL interactions can have therapeutic potential and SSL based derivatives might prove useful in treatment of cancer and destructive inflammatory diseases.
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. k.j.koymans@umcutrecht.nl.
authors.forename: Kirsten J
authors.initials: KJ
authors.lastname: Koymans
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. A.Bisschop@umcutrecht.nl.
authors.forename: Adinda
authors.initials: A
authors.lastname: Bisschop
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. M.M.Vughs@umcutrecht.nl.
authors.forename: Mignon M
authors.initials: MM
authors.lastname: Vughs
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. K.Kessel@umcutrecht.nl.
authors.forename: Kok P M
authors.initials: KP
authors.lastname: van Kessel
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. C.J.C.deHaas@umcutrecht.nl.
authors.forename: Carla J C
authors.initials: CJ
authors.lastname: de Haas
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. J.vanStrijp@umcutrecht.nl.
authors.forename: Jos A G
authors.initials: JA
authors.lastname: van Strijp
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D001426:Bacterial Proteins; D061965:Matrix Metalloproteinase Inhibitors; C000614070:SSL5 protein, Staphylococcus aureus; D020782:Matrix Metalloproteinases
keywords: S. aureus; enzyme-inhibitor; immune evasion; innate immunity; matrix metalloproteinase; neutrophil; staphylococcal superantigen-like proteins