Extracellular matrix components in the pathogenesis of type 1 diabetes

Abstract

Type 1 diabetes (T1D) results from progressive immune cell-mediated destruction of pancreatic β cells. As immune cells migrate into the islets, they pass through the extracellular matrix (ECM). This ECM is composed of different macromolecules localized to different compartments within and surrounding islets; however, the involvement of this ECM in the development of human T1D is not well understood. Here, we summarize our recent findings from human and mouse studies illustrating how specific components of the islet ECM that constitute basement membranes and interstitial matrix of the islets, and surprisingly, the intracellular composition of islet β cells themselves, are significantly altered during the pathogenesis of T1D. Our focus is on the ECM molecules laminins, collagens, heparan sulfate/heparan sulfate proteoglycans, and hyaluronan, as well as on the enzymes that degrade these ECM components. We propose that islet and lymphoid tissue ECM composition and organization are critical to promoting immune cell activation, islet invasion, and destruction of islet β cells in T1D.

Figure 1. Altered morphologic patterns of specific islet extracellular matrix components in T1D

(a) Disruption of the peri-islet basement membrane (BM) in T1D. (A) Immunofluorescence staining of the healthy human pancreatic islet for collagen type III to visualize the interstitial matrix (IM) of the peri-islet capsule and pan-laminin to mark the peri-islet basement membrane (BM). (B) In the inflamed islet of a T1D patient, the peri-islet BM staining (arrows) is lost only at the sites of leukocyte penetration into the islet. Insets on the right hand side show high magnifications of healthy and T1D pancreatic islets. (C) In long-term T1D islets, which are insulin-negative/glucagon-positive, the peri-islet BM is regenerated once inflammation has subsided, as shown by immunofluorescence for pan-laminin. BV = blood vessels, A = acinar BM. Scale bars: 100 µm. (b) Hyaluronan (HA) accumulates in human pancreatic islets and insulitis areas, and lymphoid tissues in T1D. HA localizes outside the endocrine cells in normal human islets (A) and accumulates along the islet microvessels in T1D (B). HA also accumulates in regions of insulitis (C), where it forms a meshwork around the CD45-positive inflammatory cells (D). HA is sparse in follicular germinal centers (GC) in normal pancreatic lymph nodes (E) while it is abundant in follicular GCs in T1D (F). HA appears to form a network in the T-cell (TC) areas in normal spleen tissues (G) and its patterns are altered in these areas in T1D (H). Scale bars: 25 µm (A–D) and 100 µm (E–H). Quantitative analysis of HA-stained areas in pancreatic islets (I) and specific regions of immune cell activation in lymphoid tissue (K) in T1D. (J) Correlation analysis between HA accumulation and prevalence of insulitis (J). Red bars and circles, diabetic tissues, blue bars, control tissues. *P < 0.005 vs. normal tissues. (c) Loss of heparan sulfate (HS) in islets of diabetic NOD mice. NOD mouse pancreas specimens show strong histochemical staining of intra-islet HS by Alcian blue in an islet without insulitis, as indicated by histological staining with hematoxylin and eosin (H&E) (A, B), intra-islet HS present in an islet with predominantly non-destructive insulitis mononuclear cells (MNCs) (C, D) and dramatic loss of HS in islet tissue with destructive insulitis post-T1D onset (E, F). Scale bar, 100 µm.

Figure 2. Schematic representation of the possible contributions of the extracellular matrix contributions to inflammatory cell infiltration of the pancreatic islet in T1D

Following islet injury, induced changes in the local environment promote an inflammatory process resulting in the migration of leukocytes from the circulation into the pancreatic islet. During this process, HA accumulates along the islet microvasculature and serves as “glue” for the leukocytes extravasating from the PCVs, causing leukocyte arrest at the islet periphery. Degrading and proteolytic enzymes released by the arrested leukocytes break down islet ECM constituents. Consequently, molecular interactions among the ECM components are destabilized, leading to disruption and finally loss of the peri-islet basement membrane allowing leukocyte invasion of the islet. Leukocyte cell surface-associated or vicinal HA and fragmented HA provide cues for leukocyte activation and phenotypic changes, further promoting islet inflammation. In addition, loss of HS from the pancreatic β cell contributes to decrease in β-cell survival.