Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion.
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.
Majors
Alana K
AK
Department of Immunology, NB30, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. majorsa@ccf.org
Austin
Richard C
RC
de la Motte
Carol A
CA
Pyeritz
Reed E
RE
Hascall
Vincent C
VC
Kessler
Sean P
SP
Sen
Ganes
G
Strong
Scott A
SA
D000818:Animals; D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion; D003106:Colon / Q000166:cytology; D016264:Dextran Sulfate / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology*; D005109:Extracellular Matrix / Q000737:chemistry; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D007962:Leukocytes / Q000166:cytology*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D014415:Tunicamycin / Q000494:pharmacology
D014415:Tunicamycin; D006820:Hyaluronic Acid; D016264:Dextran Sulfate