Endoplasmic Reticulum Stress Induces Hyaluronan Deposition and Leukocyte Adhesion

Abstract

There is mounting evidence that perturbations in endoplasmic reticulum (ER) function play a key role in the pathogenesis of a broad range of diseases. We have examined the ability of ER stress to modulate leukocyte binding to colonic and aortic smooth muscle cells. In vitro, control smooth muscle cells bind few leukocytes, but treatment with compounds that induce ER stress, including tunicamycin, A23187, and thapsigargin, promotes leukocyte binding. Likewise, dextran sulfate, another agent capable of inducing ER stress and promoting inflammation in vivo, strongly induces leukocyte adhesion. The bound leukocytes are released by hyaluronidase treatment, indicating a critical role for hyaluronan-containing structures in mediating leukocyte binding. Affinity histochemistry demonstrated that hyaluronan accumulates and is present in cable-like structures in the treated, but not the untreated, cultures and that these structures serve as attachment sites for leukocytes. Hyaluronan-rich regions of both murine and human inflamed colon contain numerous cells that stain intensely for ER-resident chaperones containing the KDEL sequence, demonstrating a relationship between ER stress and hyaluronan deposition in vivo. These results indicate that ER stress may contribute to chronic inflammation by forming a hyaluronan-rich extracellular matrix that is conducive to leukocyte binding.

Hyaluronan-dependent pericellular matrix☆

“…inflammation, viral infection, endoplasmic reticulum (ER) stress and hyperglycemia] and these fibers have specific leukocyte-binding properties [38,[44][45][46][47]. The hyaluronan chains from one cell often merge with those from other cells to form extremely large cables that can span many cell lengths.…”

“…It has been proposed that the presentation of hyaluronan in a crosslinked form leads to receptor clustering on leukocytes (or co-receptor engagement through the presence of accessory molecules on the cables) which would promote adhesion [32,47]. It has been suggested that this may be proinflammatory, with the cables acting as distress signals that might perpetuate chronic inflammation [45]. Others have suggested that the cables could be anti-inflammatory and control leukocyte activation by preventing adhesion through ICAM-1 [48], VCAM-1 or VLA-4 [49], or by preventing loss of matrix [32,47].…”

“…Long cables are not typically seen on the leading lamellipodia of migrating fibroblasts, indicating that the large cable structures are not necessarily required for locomotion, and may actually impede migration ( [50] and Evanko and Wight, unpublished observation). The activation of latent hyaluronan synthesis activity from predominantly perinuclear regions, particularly under conditions of ER stress suggests that cable formation may be initiated in the perinuclear and or endoplamic reticulum membranes [45,47]. This can give rise to hyaluronan cable-based nuclear interconnections that can span vast distances, forming novel sort of mechanochemical intercellular network that may serve an important role during inflammation.…”

Hyaluronan Structures Synthesized by Rat Mesangial Cells in Response to Hyperglycemia Induce Monocyte Adhesion

“…This suggests that different cellular responses have evolved to produce a matrix with information that elicits a host defense response by engaging and activating inflammatory cells. Recent studies (49) have shown that one mechanism for initiating the hyaluronan adhesive structures is the cell response to endoplasmic reticulum stress. The fact that the inflammatory FIG.…”

Proinflammatory Cytokines Induce Hyaluronan Synthesis and Monocyte Adhesion in Human Endothelial Cells through Hyaluronan Synthase 2 (HAS2) and the Nuclear Factor-κB (NF-κB) Pathway

“…Interestingly, dividing cells in hyperglycemia initiate HA synthesis in intracellular compartments (endoplasmic reticulum/Golgi/transport vesicles), which induces autophagy and cyclin D3 responses that initiate formation of HA cable structures after completion of cell division (9). This suggests that HA synthases located in these intracellular compartments can be activated and utilize the UDP-sugar substrates in the cytosol during HAS transport to and/or from the plasma membrane where it is normally active (6,10,11). Such HA cables have been described both in vitro and in vivo and appear to be associated to smooth muscle cells in gut mucosa of Crohn disease patients, in the lung of asthmatic patients, and in glomeruli of kidneys in the streptozotocin diabetic rat model (6).…”