Universität zu Köln

Jonas, Anna, Thiem, Stefan, Kuhlmann, Tanja, Wagener, Raimund, Aszodi, Attila, Nowell, Cameron ORCID: 0000-0002-8662-9840, Hagemeier, Mann, Laverick, Louise, Perreau, Victoria, Jokubaitis, Vilija, Emery, Ben, Kilpatrick, Trevor ORCID: 0000-0003-3999-085X, Butzkueven, Helmut ORCID: 0000-0003-3940-8727 and Gresle, Melissa (2014). Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation. J. Clin. Invest., 124 (11). S. 5042 - 5057. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

In patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE), inflammatory axonal injury is a major determinant of disability; however, the drivers of this injury are incompletely understood. Here, we used the EAE model and determined that the extracellular matrix protein matrilin-2 (MATN2) is an endogenous neuronal molecule that is regulated in association with inflammatory axonal injury. Compared with WT mice, mice harboring a deletion of Matn2 exhibited reduced disease severity and axon damage following induction of EAE. Evaluation of neuron-macrophage cocultures revealed that exogenous MATN2 specifically signals through TLR4 and directly induces expression of proinflammatory genes in macrophages, promoting axonal damage. Moreover, the MATN2-induced proinflammatory response was attenuated greatly in macrophages from Myd88 KO mice. Examination of brain sections from patients with MS revealed that MATN2 is expressed in lesions but not in normal-appearing white matter. Together, our results indicate that MATN2 is a deleterious endogenous neuroaxonal injury response signal that activates innate immune cells and could contribute to early axonal damage in CNS inflammatory diseases like MS.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Jonas, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiem, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuhlmann, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagener, Raimund UNSPECIFIED UNSPECIFIED UNSPECIFIED Aszodi, Attila UNSPECIFIED UNSPECIFIED UNSPECIFIED Nowell, Cameron UNSPECIFIED orcid.org/0000-0002-8662-9840 UNSPECIFIED Hagemeier, Mann UNSPECIFIED UNSPECIFIED UNSPECIFIED Laverick, Louise UNSPECIFIED UNSPECIFIED UNSPECIFIED Perreau, Victoria UNSPECIFIED UNSPECIFIED UNSPECIFIED Jokubaitis, Vilija UNSPECIFIED UNSPECIFIED UNSPECIFIED Emery, Ben UNSPECIFIED UNSPECIFIED UNSPECIFIED Kilpatrick, Trevor UNSPECIFIED orcid.org/0000-0003-3999-085X UNSPECIFIED Butzkueven, Helmut UNSPECIFIED orcid.org/0000-0003-3940-8727 UNSPECIFIED Gresle, Melissa UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-424699
DOI:	10.1172/JCI71385
Journal or Publication Title:	J. Clin. Invest.
Volume:	124
Number:	11
Page Range:	S. 5042 - 5057
Date:	2014
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	1558-8238
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LEUCINE-RICH PROTEOGLYCANS; TOLL-LIKE; EXTRACELLULAR-MATRIX; MULTIPLE-SCLEROSIS; GENE-EXPRESSION; BIGLYCAN; PROTEIN; INJURY; CELLS; DEMYELINATION Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42469