Tissue transglutaminase in marmoset experimental multiple sclerosis: discrepancy between white and grey matter.

Nathaly Espitia Pinzon,Jan Bauer,Anne-Marie Van Dam,Esther Stroo,Bert A ‘T Hart,John G J M Bol,Benjamin Drukarch

doi:10.1371/journal.pone.0100574

Nathaly Espitia Pinzon, Jan Bauer + Show 5 more

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https://doi.org/10.1371/journal.pone.0100574

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Abstract

Infiltration of leukocytes is a major pathological event in white matter lesion formation in the brain of multiple sclerosis (MS) patients. In grey matter lesions, less infiltration of these cells occur, but microglial activation is present. Thus far, the interaction of β-integrins with extracellular matrix proteins, e.g. fibronectin, is considered to be of importance for the influx of immune cells. Recent in vitro studies indicate a possible role for the enzyme tissue Transglutaminase (TG2) in mediating cell adhesion and migration. In the present study we questioned whether TG2 is present in white and grey matter lesions observed in the marmoset model for MS. To this end, immunohistochemical studies were performed. We observed that TG2, expressed by infiltrating monocytes in white matter lesions co-expressed β1-integrin and is located in close apposition to deposited fibronectin. These data suggest an important role for TG2 in the adhesion and migration of infiltrating monocytes during white matter lesion formation. Moreover, in grey matter lesions, TG2 is mainly present in microglial cells together with some β1-integrin, whereas fibronectin is absent in these lesions. These data imply an alternative role for microglial-derived TG2 in grey matter lesions, e.g. cell proliferation. Further research should clarify the functional role of TG2 in monocytes or microglial cells in MS lesion formation.

Highlights

Multiple Sclerosis (MS) is a chronic, inflammatory demyelinating disease of the human central nervous system (CNS), affecting mostly young adults in the prime of their lives [1]
There is a debate on the immunological versus neurodegenerative origin of MS [4,5,6], it is well-established that the entry of leukocytes into the CNS is an important event in the pathophysiology of MS [7,8], in addition to glial cell activation [9,10,11,12]
extracellular matrix (ECM) proteins are generally important because they play a role in the recruitment of inflammatory cells by interacting with integrins expressed on activated leukocytes [26,27,28]

Summary

Introduction

Multiple Sclerosis (MS) is a chronic, inflammatory demyelinating disease of the human central nervous system (CNS), affecting mostly young adults in the prime of their lives [1]. ECM proteins are generally important because they play a role in the recruitment of inflammatory cells by interacting with integrins expressed on activated leukocytes [26,27,28] This interaction occurs via the recognition site amino acid motif Arg-Gly-Asp (RGD) that can be found within FN [29] and many other matrix proteins [30]. TG2 is expressed in the cytoplasm or surface of a wide variety of cells, and can be deposited in the ECM [32] This enzyme, when activated, is able to bind and cross-link several ECM proteins, though its interaction with FN is best characterized [33].

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