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 5

Matn2 deletion reduces EAE disease severity and proinflammatory gene expression in vivo and in vitro.

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Matn2 deletion reduces EAE disease severity and proinflammatory gene exp...
(A) Significantly reduced disease severity (EAE grades, mean ± SEM) at day 21 in Matn2 KO mice compared with WT mice. Data presented are averaged from 4 independent cohorts with 20 to 40 mice and a total number of 60 mice per genotype. All 4 cohorts showed significantly reduced disease severity in Matn2 KO mice. ***P < 0.001, Mann-Whitney rank-sum test. (B) Survival of EAE-induced WT and Matn2 KO mice (days 0–22) shows significantly greater survival of Matn2 KO mice (n = 60 per genotype). ***P < 0.001, log-rank test. (C) Comparison of lesion size and cross-sectional cord area (%) with inflammatory lesions in the lumbar spinal cords (mean ± SEM) in Matn2 KO and WT mice in acute EAE (n = 10 per genotype). **P < 0.01, Student’s t test. (D) Quantification of IBA-1–positive macrophages, CD3-positive T cells, NG2-positive oligodendroglia, and GFAP-positive astrocyte density (mean ± SEM) in the lumbar spinal cords of WT and Matn2 KO mice (acute EAE) (n = 10 per cohort). *P < 0.05, Student’s t test. (E and F) Expression of inflammation-associated genes (mean ± SEM, qRT-PCR) in whole spinal cords from acute EAE WT and Matn2 KO mice (n = 4–6 per group). ****P < 0.0001, ***P < 0.001, **P < 0.01, P ≥ 0.5 = not significant, Student’s t test. (G) Dose response of induced expression (mean ± SEM) of inflammation-associated cytokine gene transcripts in cultured bone marrow–derived macrophages after addition of recombinant MATN2 for 24 hours (n = 3 cultures per condition, 3 independent experiments). Results are shown relative to untreated controls (dotted line). ***P < 0.001, **P < 0.01, P ≥ 0.5 = not significant), 1-way ANOVA.