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REVIEW ARTICLE

Molecular mechanisms responsible for transglutaminase 2 involvement in the multiple sclerosis etiopathogenesis and its possible use as a neuroinflammation biomarker

Rosa Giacca1 ,  Maria Preziosi1 ,  Vittorio Gentile1*
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1 Department of Precision Medicine, School of Medicine and Surgery, University of Campania “Luigi Vanvitelli”, Naples , Italy
EJMO, 026170189 https://doi.org/10.36922/EJMO026170189
Received: 21 April 2026 | Revised: 2 August 2026 | Accepted: 24 August 2026 | Published online: 15 September 2026
(This article belongs to the Special Issue Biochemistry of neuroinflammation)
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Introduction: Transglutaminase 2 (TG2) is a ubiquitous enzyme involved in extracellular matrix remodeling, cell adhesion, signal transduction, and modulation of immune responses. While its role in celiac disease is well established, increasing evidence supports its involvement in the pathogenesis of multiple sclerosis (MS).

Objectives: The objectives of this review are to describe the molecular mechanisms responsible for TG2 involvement in the multiple sclerosis etiopathogenesis and to evaluate its potential as a neuroinflammation biomarker.

Methods: The literature on the involvement of TG2 in MS was reviewed, with particular attention to its molecular mechanisms, expression in central and peripheral immune cells, association with disease activity and progression, and potential role as a biomarker of neuroinflammation.

Results: TG2 has been detected in monocytes and macrophages within demyelinating lesions, is induced in astrocytes by pro-inflammatory mediators, and is expressed in neurons and endothelial cells under neuroinflammatory conditions. Its localization in astrocytes within MS plaques further supports a role in sustaining neuroinflammation. Modulation of TG2 activity influences immune cell trafficking across the blood–brain barrier and regulates microglial and macrophage polarization. In patients with MS, altered TG2 expression and splicing isoforms in peripheral blood mononuclear cells are associated with disease activity, progression, and specific monocytic functional profiles. Preliminary findings in individuals with radiologically isolated syndrome suggest that peripheral TG2 expression may serve as an indicator of subclinical neuroinflammation.

Conclusion: Overall, TG2 emerges as a promising biomarker in MS, potentially complementing established neuroaxonal markers and improving phenotypic stratification. Further validation of its diagnostic and prognostic value will require large prospective studies integrating multi-omics approaches and advanced neuroimaging within a precision medicine framework.

 

Keywords
Transglutaminase 2
Multiple sclerosis
Biomarkers
Neuroinflammation
Peripheral blood mononuclear cells
Gene expression
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
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