A complex interplay between the extracellular matrix and the innate immune response to microbial pathogens

Abstract

The role of the host extracellular matrix (ECM) in infection tends to be neglected. However, the complex interactions between invading pathogens, host tissues and immune cells occur in the context of the ECM. On the pathogen side, a variety of surface and secreted molecules, including microbial surface components recognizing adhesive matrix molecules and tissue-degrading enzymes, are employed that interact with different ECM proteins to effectively establish an infection at specific sites. Microbial pathogens can also hijack or misuse host proteolytic systems to modify the ECM, evade immune responses or process biologically active molecules such as cell surface receptors and cytokines that direct cell behaviour and immune defence. On the host side, the ECM composition and three-dimensional ultrastructure undergo significant modifications, which have a profound impact on the specific signals that the ECM conveys to immune cells at the forefront of infection. Unexpectedly, activated immune cells participate in the remodelling of the local ECM by synthesizing ECM glycoproteins, proteoglycans and collagen molecules. The close interplay between the ECM and the innate immune response to microbial pathogens ultimately affects the outcome of infection. This review explores and discusses recent data that implicate an active role for the ECM in the immune response to infection, encompassing antimicrobial activities, microbial recognition, macrophage activation, phagocytosis, leucocyte population balance, and transcriptional and post-transcriptional regulation of inflammatory networks, and may foster novel antimicrobial approaches.

Keywords: extracellular matrix; immunity; infection.

Figure 1

Mindin, lumican and galectin‐3: three extracellular sentinels. Mindin, lumican and galectin‐3 recognize and bind to sugar moieties found in the cell wall of several types of bacteria. All of them promote phagocytosis of bacteria by macrophages. Mindin binds to bacteria, causes their opsonization and agglutination, and facilitates their phagocytosis by macrophages. Mindin also induces the synthesis of pro‐inflammatory cytokines by these cells. Lumican instead interacts with CD14 on the surface of macrophages, promoting CD14‐TLR4‐mediated responses to lipopolysaccharide (LPS) and CD14‐mediated phagocytosis.

Figure 2

Multiple functions of the extracellular matrix (ECM) in the immune response to infection. Recognition of pathogen‐associated molecular patterns by macrophages through pattern recognition receptors (PRRs) and by ECM components is shown. Pathogen binding to ECM molecules such as fibronectin helps host colonization. Degradation of the ECM through microbial tissue‐degrading enzymes or host matrix metalloproteases (MMPs) activated by pathogen facilitates host invasion. To establish the infection, pathogens can also hijack host proteolytic systems such as the plasminogen–plasmin system and evade innate immune responses by binding to ECM components such as vitronectin. Fibroblasts in the interstitial ECM produce and secrete ECM proteins, MMPs and higher levels of lysyl oxidase (LOX), which cross‐links collagen fibres, increasing ECM stiffness. Pathogen‐mediated activation of macrophages triggers inflammatory signalling pathways such as the nuclear factor‐κB (NF‐κB) pathway, which culminates in the synthesis of cytokines, MMPs and microRNAs. Activated macrophages synthesize also ECM components such as decorin and tenascin‐C, which regulate the biosynthesis of miR‐21 and miR‐155 and generate positive feedback loops that propagate inflammation.