Mast cells protect from post-traumatic spinal cord damage in mice by degrading inflammation-associated cytokines via mouse mast cell protease 4.
Mast cells (MCs) are found abundantly in the central nervous system and play a complex role in neuroinflammatory diseases such as multiple sclerosis and stroke. In the present study, we show that MC-deficient Kit(W-sh/W-sh) mice display significantly increased astrogliosis and T cell infiltration as well as significantly reduced functional recovery after spinal cord injury compared to wildtype mice. In addition, MC-deficient mice show significantly increased levels of MCP-1, TNF-α, IL-10 and IL-13 protein levels in the spinal cord. Mice deficient in mouse mast cell protease 4 (mMCP4), an MC-specific chymase, also showed increased MCP-1, IL-6 and IL-13 protein levels in spinal cord samples and a decreased functional outcome after spinal cord injury. A degradation assay using supernatant from MCs derived from either mMCP4(-/-) mice or controls revealed that mMCP4 cleaves MCP-1, IL-6, and IL-13 suggesting a protective role for MC proteases in neuroinflammation. These data show for the first time that MCs may be protective after spinal cord injury and that they may reduce CNS damage by degrading inflammation-associated cytokines via the MC-specific chymase mMCP4.
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Sofie
S
Nelissen
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Tim
T
Vangansewinkel
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Nathalie
N
Geurts
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Lies
L
Geboes
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Evi
E
Lemmens
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Pia M
PM
Vidal
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Stefanie
S
Lemmens
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Leen
L
Willems
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Francesco
F
Boato
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Dearbhaile
D
Dooley
Dept. of Dermatology and Allergy, Allergie-Centrum-Charité, Charité-Universitätsmedizin Berlin, Germany.
Debora
D
Pehl
Dept. of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Gunnar
G
Pejler
Dept. of Dermatology and Allergy, Allergie-Centrum-Charité, Charité-Universitätsmedizin Berlin, Germany.
Marcus
M
Maurer
Dept. of Dermatology and Allergy, Allergie-Centrum-Charité, Charité-Universitätsmedizin Berlin, Germany.
Martin
M
Metz
Dept. of Morphology & Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium. Electronic address: sven.hendrix@uhasselt.be.
Sven
S
Hendrix
D000818:Animals; D001253:Astrocytes / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008124:Locomotion / Q000502:physiology; D008407:Mast Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012697:Serine Endopeptidases / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism; D013904:Thoracic Vertebrae / Q000293:injuries
D016207:Cytokines; D018836:Inflammation Mediators; D012697:Serine Endopeptidases; C066932:mast cell protease 4
BMCMCs; BMS; EAE; GFAP; IL; IL-10; IL-13; IL-6; Iba-1; Inflammation; MBP; MCP-1; MCs; MS; Mast cell; RT; SCI; SN; Spinal cord injury; TNF-α; WT; basso mouse scale; bone marrow-derived cultured mast cells; experimental autoimmune encephalomyelitis; glial fibrillary acidic protein; interleukin; ionized calcium binding adaptor molecule 1; mMCP4; mast cells; monocyte chemoattractant protein 1; mouse mast cell protease 4; multiple sclerosis; myelin basic protein; room temperature; spinal cord injury; supernatants; tumor necrosis factor α; wildtype