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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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Research Article Neuroscience

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

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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.

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 4

MATN2 is released from neurons following axonal injury in spinal cord lesions.

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MATN2 is released from neurons following axonal injury in spinal cord le...
(A) Colabeling for MATN2, synaptophysin, and pan-neurofilament (NF) (top) in acute spinal cord lesions showing clear intraaxonal as well as extraaxonal MATN2 expression. Scale bar: 12.5 μm (top); 1.5 μm (bottom). (B) Confocal 3D image showing colabeling for MATN2 and neurofilament (NF) in an acute spinal cord lesion. Scale bar: 1.5 μm. (C) Matn2 expression (mean ± SEM, qRT-PCR) in mono- and cocultures following 24-hour LPS addition shows increased Matn2 expression in LPS-treated cocultures (n = 6–9 per group). Gene expression is shown relative to untreated cultures. ***P < 0.001, P ≥ 0.5 = not significant, 2-way ANOVA. (D) Immunoblot analysis reveals specific MATN2 protein expression in WT neuron (WT n) cultures compared with KO controls (KO n) and is increased in cocultures following LPS addition (24 hours). WT m, WT macrophage; rec. MATN2, recombinant MATN2. (E) Colabeling for MATN2 and IBA-1 or GFAP, RIP, or CD3 in acute spinal cord lesions demonstrates close association of MATN2 with macrophages (inset). No colocalization was detected. Nuclei were visualized with DAPI. Scale bar: 10 μm; 2.5 μm (inset).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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