Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation
Anna Jonas, … , Helmut Butzkueven, Melissa Gresle
Anna Jonas, … , Helmut Butzkueven, Melissa Gresle
Published October 20, 2014
Citation Information: J Clin Invest. 2014;124(11):5042-5056. https://doi.org/10.1172/JCI71385.
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Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation

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.

Authors

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

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Figure 1

Axonal injury in the spinal cords of EAE mice induces gene expression changes in the motor cortices.

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Axonal injury in the spinal cords of EAE mice induces gene expression ch...
(A) Expression of GFAP and IBA-1 in the motor cortices (mc) of healthy and EAE mice is consistent with induction of a glial response in EAE cortices. Nuclei were visualized with DAPI (blue). Scale bar: 100 μm (left); 25 μm (left inset); 200 μm (right); 50 μm (right inset). (B) Fold changes (P < 0.05) of genes encoding ECM-related proteins differentially expressed in the motor cortices of EAE mice compared with healthy controls identified with microarray analysis. (C) Gene expression changes (mean ± SEM, qRT-PCR) for indicated transcripts in the motor cortices of EAE mice (n = 4–8 per group) relative to healthy control mice (dotted line). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, Student’s t test.