Monocyte behaviour and tissue transglutaminase expression during experimental autoimmune encephalomyelitis in transgenic CX3CR1gfp/gfp mice

Abstract

Leukocyte infiltration into the central nervous system (CNS) is a key pathological feature in multiple sclerosis (MS) and the MS animal model experimental autoimmune encephalomyelitis (EAE). Recently, preventing leukocyte influx into the CNS of MS patients is the main target of MS therapies and insight into cell behaviour in the circulation is needed for further elucidation of such therapies. In this study, we aimed at in vivo visualization of monocytes in a time-dependent manner during EAE. Using intravital two-photon microscopy (IVM), we imaged CX3CR1gfp/gfp mice during EAE, visualizing CX3CR1-GFP+ monocytes and their dynamics in the spinal cord vasculature. Our observations showed that intraluminal crawling of CX3CR1-GFP+ monocytes increased even before the clinical onset of EAE due to immunization of the animals. Furthermore, intraluminal crawling remained elevated during ongoing clinical disease. Besides, the displacement of these cells was larger during the peak of EAE compared to the control animals. In addition, we showed that the enzyme tissue transglutaminase (TG2), which is present in CNS-infiltrated cells in MS patients, is likewise found in CX3CR1-GFP+ monocytes in the spinal cord lesions and at the luminal side of the vasculature during EAE. It might thereby contribute to adhesion and crawling of monocytes, facilitating extravasation into the CNS. Thus, we put forward that interference with monocyte adhesion, by e.g. inhibition of TG2, should be applied at a very early stage of EAE and possibly MS, to effectively combat subsequent pathology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-016-2359-0) contains supplementary material, which is available to authorized users.

Characterization of Transglutaminase 2 activity inhibitors in monocytes in vitro and their effect in a mouse model for multiple sclerosis

“…In the present study we used two irreversible TG2 activity inhibitors to measure their effect on disease symptoms, severity and pathology in a mouse EAE model for multiple sclerosis. Our previous studies identified TG2 as a possible therapeutical target in a rat chronic relapsing EAE model in which TG2 inhibition reduced cellular infiltration as well as disease symptoms [ 13 , 34 ]. Moreover, EAE induced in C57BL/6 mice has previously been shown to be, at least partly, mediated by TG2 [ 13 ].…”

Tissue Transglutaminase Expression Associates With Progression of Multiple Sclerosis

“… 29 – 31 Previous research has highlighted the possible role for TG2 in the pathogenesis of MS 16 , 32 as well as in its animal model EAE. 15 , 17 , 33 In search for potential novel blood-derived biomarkers, this study reports on PBMC-derived TG2 mRNA levels in patients with MS, and in its clinical subtypes, in relation to markers of disease activity and progression.…”

Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System

“…In MS and EAE, monocytes/MdMs also accumulate in large numbers in the SAS following extravasation from the leptomeningeal vasculature or from the ChP and CSF-filled ventricles. Infiltration through leptomeningeal vessels follows increased intraluminal monocyte crawling and expression of the enzyme tissue transglutaminase 2 ( 261 ), known for its involvement in cell adhesion to fibronectin, a glycoprotein released by endothelial cells and pericytes ( 262 ).…”