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
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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Research Article Neuroscience

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 8

MATN2 signals through TLR 4.

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MATN2 signals through TLR 4. (A) Screening for MATN2-triggered (2 μg/ml)...
(A) Screening for MATN2-triggered (2 μg/ml) activation of the alkaline phosphatase reporter via TLR/NF-κB signaling in genetically modified HEK293 cells expressing the indicated type of TLR (black bars). Alkaline phosphatase activity (arbitrary units) is used as an indicator for TLR stimulation. As positive control, cell lines were induced with a receptor-specific ligand. TLR2, heat-killed Listeria monocytogenes at 108 cells/ml; TLR3, poly(I:C) at 1 μg/ml; TLR4, E. coli K12 LPS at 100 ng/ml; TLR5, S. typhimurium flagellin at 100 ng/ml; TLR7, CL097 at 1 μg/ml; TLR8, CL075 at 10 μg/ml + poly(dT) 10 μM; and TLR9, CpG ODN 1826 at 100 ng/ml. Noninduced TLR clones were used as negative controls (white bars), and a HEK293 cell line expressing only alkaline phosphatase but not TLR4 was used as specific TLR4 negative control (TLR4–). (B and C) Fold induction in alkaline phosphatase triggered by (B) 2 μg/ml MATN2 or 100 ng/ml LPS or by (C) the indicated doses of MATN2 or LPS. Note that the response elicited by 2,000 ng/ml MATN2 is significantly greater than that of the trace LPS concentration of 0.01 ng/ml (P = 0.003). ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05.