Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation

Anna Jonas, Stefan Thiem, Tanja Kuhlmann, Raimund Wagener, Attila Aszodi, Cameron Nowell, Karin Hagemeier, Louise Laverick, Victoria Perreau, Vilija Jokubaitis, Ben Emery, Trevor Kilpatrick, Helmut Butzkueven, Melissa Gresle

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 neuronmacrophage 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.

Original languageEnglish (US)
Pages (from-to)5042-5056
Number of pages15
JournalJournal of Clinical Investigation
Volume124
Issue number11
DOIs
StatePublished - Nov 3 2014
Externally publishedYes

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Matrilin Proteins
Autoimmunity
Autoimmune Experimental Encephalomyelitis
Multiple Sclerosis
Wounds and Injuries
Macrophages
Extracellular Matrix Proteins
Central Nervous System Diseases
Coculture Techniques
Axons
Gene Expression
Brain

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Jonas, A., Thiem, S., Kuhlmann, T., Wagener, R., Aszodi, A., Nowell, C., ... Gresle, M. (2014). Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation. Journal of Clinical Investigation, 124(11), 5042-5056. https://doi.org/10.1172/JCI71385

Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation. / Jonas, Anna; Thiem, Stefan; Kuhlmann, Tanja; Wagener, Raimund; Aszodi, Attila; Nowell, Cameron; Hagemeier, Karin; Laverick, Louise; Perreau, Victoria; Jokubaitis, Vilija; Emery, Ben; Kilpatrick, Trevor; Butzkueven, Helmut; Gresle, Melissa.

In: Journal of Clinical Investigation, Vol. 124, No. 11, 03.11.2014, p. 5042-5056.

Research output: Contribution to journalArticle

Jonas, A, Thiem, S, Kuhlmann, T, Wagener, R, Aszodi, A, Nowell, C, Hagemeier, K, Laverick, L, Perreau, V, Jokubaitis, V, Emery, B, Kilpatrick, T, Butzkueven, H & Gresle, M 2014, 'Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation', Journal of Clinical Investigation, vol. 124, no. 11, pp. 5042-5056. https://doi.org/10.1172/JCI71385
Jonas, Anna ; Thiem, Stefan ; Kuhlmann, Tanja ; Wagener, Raimund ; Aszodi, Attila ; Nowell, Cameron ; Hagemeier, Karin ; Laverick, Louise ; Perreau, Victoria ; Jokubaitis, Vilija ; Emery, Ben ; Kilpatrick, Trevor ; Butzkueven, Helmut ; Gresle, Melissa. / Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 11. pp. 5042-5056.
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