Mast cells protect from post-traumatic spinal cord inflammation in mice by degrading inflammation-associated cytokines via mouse mast cell protease 4

Abstract

Purpose/Objective: It becomes increasinglyclear that mast cells (MCs) are not only key players in allergic diseases (e.g.asthma), but seem to play a complex role in neuroinflammatory diseases such as multiple sclerosis and stroke. However, their role during and after mechanical CNS trauma is not clear. In the present study, we have investigated the effectsof MC-deficiency on the histological and clinical outcome after spinal cordhemisection at thoraic level T8 resulting in a complete transection of the dorsomedial and ventral corticospinal tract. Functional recovery in SCI mice was tested with the Basso Mouse Scale. Spinal cord sections were analyzed by immunofluorescence. RTPCR and Western blotting were used to analyze cytokine/chemokine mRNA and protein levels. In degradation assays murine recombinant IL-1b, IL-4, IL-6, IL-10, IL-13, TNF-a and MCP-1 were incubated with supernatant from BMCMC derived from either C57BL/6 or from mMCP4 -/-mice. Cleaved fragments were identified using tris-tricine SDS-PAGE and analyzed by intensity analysis. Results: We show that MC-deficient kitW-sh/W-sh mice display significantly increased astrogliosis and T cell infiltration as well as significantly reduced clinical outcome after SCI compared to wildtype mice. In addition, MC-deficient mice show significantly increased levels of MCP-1, TNF-a, IL-10 and IL-13 protein levels in the spinal cord after SCI. Mice deficient in mMCP-4, a 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 SCI. A degradation assay using supernatant from MCs derived from either mMCP4 -/- or wildtype mice revealed that mMCP-4 cleaves MCP-1, IL-6 and IL-13, suggesting a protective role for MC proteases in neuroinflammation. These data indicate that MCs may be protective after SCI and that they may reduce CNS inflammation by degrading inflammation-associated cytokines via the mast cell-specific chymase mMCP-4. Conclusions: In summary, our results suggest a new and complex mechanism how MCs and their proteases may protect the CNS from exacerbated and/or chronic inflammation after damage.

Publication appears at doi: 10.1111/imm.12002