Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

Abstract

Chronic liver disease when accompanied by underlying fibrosis, is characterized by an accumulation of extracellular matrix (ECM) proteins and chronic inflammation. Although traditionally considered as a passive and largely architectural structure, the ECM is now being recognized as a source of potent damage-associated molecular pattern (DAMP)s with immune-active peptides and domains. In parallel, the ECM anchors a range of cytokines, chemokines and growth factors, all of which are capable of modulating immune responses. A growing body of evidence shows that ECM proteins themselves are capable of modulating immunity either directly via ligation with immune cell receptors including integrins and TLRs, or indirectly through release of immunoactive molecules such as cytokines which are stored within the ECM structure. Notably, ECM deposition and remodeling during injury and fibrosis can result in release or formation of ECM-DAMPs within the tissue, which can promote local inflammatory immune response and chemotactic immune cell recruitment and inflammation. It is well described that the ECM and immune response are interlinked and mutually participate in driving fibrosis, although their precise interactions in the context of chronic liver disease are poorly understood. This review aims to describe the known pro-/anti-inflammatory and fibrogenic properties of ECM proteins and DAMPs, with particular reference to the immunomodulatory properties of the ECM in the context of chronic liver disease. Finally, we discuss the importance of developing novel biotechnological platforms based on decellularized ECM-scaffolds, which provide opportunities to directly explore liver ECM-immune cell interactions in greater detail.

Human Three-Dimensional Hepatic Models: Cell Type Variety and Corresponding Applications

“…Thus, it is superior in modeling the liver sinusoid, creating a more realistic and dynamic zone-specific culture environment (Gupta et al, 2016). In vivo, a hepatic extracellular matrix (ECM) supports structure and signaling trafficking, maintains hepatocyte polarity, and provides the microenvironment for interaction of hepatocyte and immune cells via integrins and other ECM receptors (Treyer and Müsch, 2013;Gissen and Arias, 2015;McQuitty et al, 2020). Owing to its essential role in maintaining hepatic function and disease progression, the ECM should be involved in the establishment of in vivo-like 3D models.…”

A Perfusion Bioreactor for Longitudinal Monitoring of Bioengineered Liver Constructs

“…The physiological environment constituted by the hepatic ECM is a tissue-specific architecture of both structural and functional proteins maintained by a precisely regulated equilibrium between synthesis and degradation [ 15 ]. The ECM harbors a range of growth factors and other matrix-associated molecules which influence cellular activity [ 16 ]. ECM also provides cells with signals for polarization, adhesion, migration, proliferation, survival and differentiation [ 17 ].…”

Effect of Uncaria rhynchophylla against Thioacetamide-Induced Acute Liver Injury in Rat

“…Moreover, we examined the expression of matrix metalloproteinase-(MMP-) 1, 2, and 8, and the tissue inhibitor of metalloproteinase-(TIMP-) 1. e extracellular matrix (ECM) is composed of collagen (95%), proteoglycans (aggrecans), elastin, laminins, and fibronectin [37]. MMPs are the primary enzymes implicated in ECM degradation, and irregular ECM turnover is involved in a variety of liver diseases [10,38]. Meanwhile, active MMPs are mainly regulated by TIMPs, the chief MMP regulator.…”