Extracellular matrix and the maintenance and loss of peripheral immune tolerance in autoimmune insulitis

Abstract

There is a growing appreciation that the extracellular matrix (ECM) contributes to both the maintenance of immune tolerance in healthy tissues and to its loss at sites of autoimmunity. Here, we review recent literature on the role of ECM and particularly the glycosaminoglycans hyaluronan and heparan sulfate in the development of autoimmune, type 1 diabetes (T1D). Data from transplant models suggest that healthy islets are embedded within an intact ECM that supports beta-cell homeostasis and provides physical and immunoregulatory barriers against immune infiltration. However, studies of human insulitis as well as the non-obese diabetic (NOD) and DORmO mouse models of T1D indicate that autoimmune insulitis is associated with the degradation of basement membrane structures, the catabolism of the islet interstitium, and the accumulation of a hyaluronan-rich, pro-inflammatory ECM. Moreover, in these models of autoimmune diabetes, either the pharmacologic inhibition of heparan sulfate catabolism, the reduction of hyaluronan synthesis, or the targeting of the pathways that sense these ECM changes can all prevent beta-cell destruction. Together these data support an emerging paradigm that in healthy islets the local ECM contributes to both immune tolerance and beta-cell homeostasis while in chronic inflammation the islet ECM is permissive to immune infiltration and beta cell destruction. Therapies that support ECM-mediated “barrier tolerance” may have potential as adjunctive agents in combination regimens designed to prevent or treat autoimmunity.

Pancreatic Tissue Proteomics Unveils Key Proteins, Pathways, and Networks Associated with Type 1 Diabetes

“…In addition, insulitis association with the accumulation of hyaluronan has been reported in islets. [ 19,20 ] Our results showed upregulation of proteins associated with ECM‐receptor interaction pathway in T1D (Figure 5B). These interactions regulate different biological processes such as cell adhesion, migration, differentiation, proliferation, and apoptosis.…”

Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity

“…The capability of miR-29c-3p to trace a more severe manifestation of T1D may be very relevant to predicting higher risks of long-term diabetic complications, as DKA at diagnosis is associated with poor long-term glycemic control [11,12]. The significant enrichment in genes involved in extracellular matrix (ECM) organization for the list of miR-29c-3p-validated mRNA targets may functionally link miRNA-increased plasmatic levels in more severe T1D patients with data, indicating that a damaged ECM in the islets concurs with the breach of β cell homeostasis and loss of physical and immunoregulatory barriers against immune cell infiltration [63,64]. This intriguing hypothesis will deserve further exploration in the future.…”

High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity

“…In vascular tissues, hyaluronan affects smooth muscle cell proliferation [20,21], endothelial cell differentiation [[22], [23], [24]] and immune cell function [6,25,26]. Thus, hyaluronan has an important role in the regulation of vascular integrity, and its shedding from endothelial glycocalyx correlates to impaired vascular integrity during injury [27,28].…”