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.

Highlights

  • Matrix metalloproteinases (MMPs) constitute a large, structurally related, family of zinc-dependent proteases with in the human system currently up to 23 distinct members described

  • To determine whether S. aureus produces additional MMP inhibitors, we broadly screened for the effects of secreted staphylococcal proteins on the activity of the two most important MMPs secreted by neutrophils: MMP8 and MMP9

  • Exposure to staphylococci induces upregulation of active MMP9 in the spleen [23], and human fibroblasts treated with culture supernatant or whole cell lysates of S. aureus show enhanced expression of many MMPs [24]

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Summary

Introduction

Matrix metalloproteinases (MMPs) constitute a large, structurally related, family of zinc-dependent proteases with in the human system currently up to 23 distinct members described. They are named after their initially described role: the turnover and degradation of extracellular matrix (ECM) components [1]. MMPs are directly implicated in bacterial infection, wound healing, and cancer cell invasiveness and they can have both anti- and pro-inflammatory effects, depending on the MMP, the situation, and the target molecule. Chemokines and cytokines can be broken down or converted to antagonists by MMPs, but in recent years, it has been realized that, during bacterial infections, MMPs are widely involved in immune cell recruitment and have been shown to facilitate cell migration to the site of inflammation through several processes [2,3,4,5]. MMPs directly affect chemoattractant molecules; chemokines can be effectively potentiated through MMP cleavage, thereby enhancing inflammation and aiding in bacterial clearance

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