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 7

Exogenous MATN2 induces proinflammatory gene expression in macrophages via TLR signaling pathways.

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Exogenous MATN2 induces proinflammatory gene expression in macrophages v...
(A) Expression of Il1b, Tnfa, and Nlrp3 in WT and Myd88 KO macrophages (mean ± SEM, qRT-PCR) following incubation with recombinant MATN2 (2 μg/ml) at indicated time points (n = 3 cultures per condition, 3 independent experiments). Results are shown relative to untreated controls (dotted line; ****P < 0.0001, **P < 0.01, *P < 0.05, 2-way ANOVA). (B) Immunoblot analysis of whole cell lysates for pro–IL-1β, pro–TNF-α, and NLRP3 of WT and MyD88 KO macrophages without or after 30, 60, and 240 minutes of MATN2 incubation. Data show 1 of 4 independent experiments with total ERK as loading control. (C) WT and MyD88 KO macrophage cultures (stained with Calcein AM) after 24-hour incubation with recombinant MATN2 (2 μg/ml). Note that only WT cells are activated following MATN2 addition. Scale bar: 25 μm. (D) Immunoblot analysis for phosphorylated NF-κB, p38, and ERK1/2 as well as total NF-κB, ERK1/2, p38, and actin of WT and Myd88 KO macrophage whole cell lysates untreated or after 10, 30, 60, and 240 minutes of MATN2 incubation. Data show 1 of 4 independent experiments.