title: 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.forename: Anna
authors.initials: A
authors.lastname: Jonas
authors.forename: Stefan
authors.initials: S
authors.lastname: Thiem
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.forename: Raimund
authors.initials: R
authors.lastname: Wagener
authors.forename: Attila
authors.initials: A
authors.lastname: Aszodi
authors.forename: Cameron
authors.initials: C
authors.lastname: Nowell
authors.forename: Karin
authors.initials: K
authors.lastname: Hagemeier
authors.forename: Louise
authors.initials: L
authors.lastname: Laverick
authors.forename: Victoria
authors.initials: V
authors.lastname: Perreau
authors.forename: Vilija
authors.initials: V
authors.lastname: Jokubaitis
authors.forename: Ben
authors.initials: B
authors.lastname: Emery
authors.forename: Trevor
authors.initials: T
authors.lastname: Kilpatrick
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
authors.forename: Melissa
authors.initials: M
authors.lastname: Gresle
mesh_terms: D000818:Animals; D001369:Axons / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D064235:Matrilin Proteins / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009044:Motor Cortex / Q000378:metabolism; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018836:Inflammation Mediators; C577542:Matn2 protein, mouse; D064235:Matrilin Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4