Sofie Nelissen

The role of mast cells in neuroinflammation

Mast cells (MCs) are densely granulated perivascular resident cells of hematopoietic origin and well known for their pathogenetic role in allergic and anaphylactic reactions. In addition, they are also involved in processes of innate and adaptive immunity. MCs can be activated in response to a wide range of stimuli, resulting in the release of not only pro-inflammatory, but also anti-inflammatory mediators. The patterns of secreted mediators depend upon the given stimuli and microenvironmental conditions, accordingly MCs have the ability to promote or attenuate inflammatory processes. Their presence in the central nervous system (CNS) has been recognized for more than a century. Since then a participation of MCs in various pathological processes in the CNS has been well documented. They can aggravate CNS damage in models of brain ischemia and hemorrhage, namely through increased blood–brain barrier damage, brain edema and hemorrhage formation and promotion of inflammatory responses to such events. In contrast, recent evidence suggests that MCs may have a protective role following traumatic brain injury by degrading pro-inflammatory cytokines via specific proteases. In neuroinflammatory diseases such as multiple sclerosis, the role of MCs seems to be ambiguous. MCs have been shown to be damaging, neuroprotective, or even dispensable, depending on the experimental protocols used. The role of MCs in the formation and progression of CNS tumors such as gliomas is complex and both positive and negative relationships between MC activity and tumor progression have been reported. In summary, MCs and their secreted mediators modulate inflammatory processes in multiple CNS pathologies and can thereby either contribute to neurological damage or confer neuroprotection. This review intends to give a concise overview of the regulatory roles of MCs in brain disease.

Mast cells protect from post-traumatic brain inflammation by the mast cell-specific chymase mouse mast cell protease-4

Mast cells (MCs) are found abundantly in the brain and the meninges and play a complex role in neuroinflammatory diseases, such as stroke and multiple sclerosis. Here, we show that MC‐deficient KitW/KitWv mice display increased neurodegeneration in the lesion area after brain trauma. Furthermore, MC‐deficient mice display significantly more brain inflammation, namely an increased presence of macrophages/microglia, as well as dramatically increased T‐cell infiltration at days 4 and 14 after injury, combined with increased astrogliosis at day 14 following injury. The number of proliferating Ki67+ macrophages/microglia and astrocytes around the lesion area is more than doubled in these MC‐deficient mice. In parallel, MC‐deficient KitW‐sh/W‐sh mice display increased presence of macrophages/microglia at day 4, and persistent astrogliosis at day 4 and 14 after brain trauma. Further analysis of mice deficient in one of the most relevant MC proteases, i.e., mouse mast cell protease 4 (mMCP‐4), revealed that astrogliosis and T‐cell infiltration are significantly increased in mMCP‐4‐knockout mice. Finally, treatment with an inhibitor of mMCP‐4 significantly increased macrophage/microglia numbers and astrogliosis. These data suggest that MCs exert protective functions after trauma, at least in part via mMCP‐4, by suppressing exacerbated inflammation via their proteases.—Hendrix, S., Kramer, P., Pehl, D., Warnke, K., Boato, F., Nelissen, S., Lemmens, E., Pejler, G., Metz, M., Siebenhaar, F., Maurer, M. Mast cells protect from post‐traumatic brain inflammation by the mast cell‐specific chymase mouse mast cell protease‐4. FASEB J. 27, 920–929 (2013). www.fasebj.org

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.

Absence of IL-1β positively affects neurological outcome, lesion development and axonal plasticity after spinal cord injury

Precise crosstalk between the nervous and immune systems is important for neuroprotection and axon plasticity after injury. Recently, we demonstrated that IL-1β acts as a potent inducer of neurite outgrowth from organotypic brain slices in vitro, suggesting a potential function of IL-1β in axonal plasticity. Here, we have investigated the effects of IL-1β on axon plasticity during glial scar formation and on functional recovery in a mouse model of spinal cord compression injury (SCI). We used an IL-1β deficiency model (IL-1βKO mice) and administered recombinant IL-1β. In contrast to our hypothesis, the histological analysis revealed a significantly increased lesion width and a reduced number of corticospinal tract fibers caudal to the lesion center after local application of recombinant IL-1β. Consistently, the treatment significantly worsened the neurological outcome after SCI in mice compared with PBS controls. In contrast, the absence of IL-1β in IL-1βKO mice significantly improved recovery from SCI compared with wildtype mice. Histological analysis revealed a smaller lesion size, reduced lesion width and greatly decreased astrogliosis in the white matter, while the number of corticospinal tract fibers increased significantly 5 mm caudal to the lesion in IL-1βKO mice relative to controls. Our study for the first time characterizes the detrimental effects of IL-1β not only on lesion development (in terms of size and glia activation), but also on the plasticity of central nervous system axons after injury.

Late blocking of peripheral TNF-α is ineffective after spinal cord injury in mice

Spinal cord injury (SCI) is characterized by different phases of inflammatory responses. Increasing evidence indicates that the early chronic phase (two to three weeks after SCI) is characterized by a dramatic invasion of immune cells and a peak of pro-inflammatory cytokine levels, such as tumor necrosis factor-α (TNF-α) derived from the injured spinal cord as well as from injured skin, muscles and bones. However, there is substantial controversy whether these inflammatory processes in later phases lead to pro-regenerative or detrimental effects. In the present study, we investigated whether the inhibition of peripheral TNF-α in the early chronic phase after injury promotes functional recovery in a dorsal hemisection model of SCI. Three different approaches were used to continuously block peripheral TNF-α in vivo, starting 14 days after injury. We administered the TNF-α blocker etanercept intraperitoneally (every second day or daily) as well as continuously via osmotic minipumps. None of these administration routes for the TNF-α inhibitor influenced locomotor restoration as assessed by the Basso mouse scale (BMS), nor did they affect coordination and strength as evaluated by the Rotarod test. These data suggest that peripheral TNF-α inhibition may not be an effective therapeutic strategy in the early chronic phase after SCI.

Oncostatin M Reduces Lesion Size and Promotes Functional Recovery and Neurite Outgrowth After Spinal Cord Injury

The family of interleukin (IL)-6 like cytokines plays an important role in the neuroinflammatory response to injury by regulating both neural as well as immune responses. Here, we show that expression of the IL-6 family member oncostatin M (OSM) and its receptor is upregulated after spinal cord injury (SCI). To reveal the relevance of increased OSM signaling in the pathophysiology of SCI, OSM was applied locally after spinal cord hemisection in mice. OSM treatment significantly improved locomotor recovery after mild and severe SCI. Improved recovery in OSM-treated mice was associated with a reduced lesion size. OSM significantly diminished astrogliosis and immune cell infiltration. Thus, OSM limits secondary damage after CNS trauma. In vitro viability assays demonstrated that OSM protects primary neurons in culture from cell death, suggesting that the underlying mechanism involves direct neuroprotective effects of OSM. Furthermore, OSM dose-dependently promoted neurite outgrowth in cultured neurons, indicating that the cytokine plays an additional role in CNS repair. Indeed, our in vivo experiments demonstrate that OSM treatment increases plasticity of serotonergic fibers after SCI. Together, our data show that OSM is produced at the lesion site, where it protects the CNS from further damage and promotes recovery.

Experimental febrile seizures increase dendritic complexity of newborn dentate granule cells

Febrile seizures (FS) are fever‐associated convulsions, being the most common seizure disorder in early childhood. A subgroup of these children later develops epilepsy characterized by a hyperexcitable neuronal network in the hippocampus. Hippocampal excitability is regulated by the hippocampal dentate gyrus (DG) where postnatal neurogenesis occurs. Experimental FS increase the survival of newborn hippocampal dentate granule cells (DGCs), yet the significance of this neuronal subpopulation to the hippocampal network remains unclear. In the current study, we characterized the temporal maturation and structural integration of these post‐FS born DGCs in the DG.

Basophils are dispensable for the recovery of gross locomotion after spinal cord hemisection injury

Basophils are the smallest population of granulocytes found in the circulation. They have crucial and nonredundant roles in allergic disorders, in protection from parasite infections, in autoimmunity, and in the regulation of type 2 immunity. They share phenotypic and functional properties with mast cells, which exert substantial protective effects after traumatic brain injury and spinal cord injury, although they are considered one of the most proinflammatory cell types in the body. In contrast, the in vivo functions of basophils in central nervous system trauma are still obscure and not well studied. In this study, we show that by comparing spinal cord injury in wild type vs. basophil‐deficient Mcpt8Cre transgenic mice, the locomotor recovery is not affected in mice depleted in basophils. In addition, no substantial differences were observed in the lesion size and in the astrocytic and macrophage/microglia reaction between both mouse strains. Hence, despite the multiple properties shared with mast cells, these data show, for the first time, to our knowledge, that basophils are dispensable for the functional recovery process after hemisection injury to the spinal cord in mice.

Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6

An important barrier for axon regeneration and recovery after traumatic spinal cord injury (SCI) is attributed to the scar that is formed at the lesion site. Here, we investigated the effect of mouse mast cell protease (mMCP) 6, a mast cell (MC)‐specific tryptase, on scarring and functional recovery after a spinal cord hemisection injury. Functional recovery was significantly impaired in both MC‐deficient and mMCP6‐knockout (mMCP62/2) mice after SCI compared with wild‐type control mice. This decrease in locomotor performance was associated with an increased lesion size and excessive scarring at the injury site. Axon growth‐inhibitory chondroitin sulfate proteoglycans and the extracellular matrix components fibronectin, laminin, and collagen IV were significantly up‐regulated in MC‐deficient and mMCP6–/– mice, with an increase in scar volume between 23 and 32%. A degradation assay revealed that mMCP6 directly cleaves fibronectin and collagen IV in vitro. In addition, gene expression levels of the scar components fibronectin, aggrecan, and collagen IV were increased up to 6.8‐fold in mMCP6–/– mice in the subacute phase after injury. These data indicate that endogenous mMCP6 has scar‐suppressing properties after SCI via indirect cleavage of axon growth‐inhibitory scar components and alteration of the gene expression profile of these factors.—Vangansewinkel, T., Geurts, N., Quanten, K., Nelissen, S., Lemmens, S., Geboes, L., Dooley, D., Vidal, P. M., Pejler, G., Hendrix, S. Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6. FASEB J. 30, 2040–2057 (2016). www.fasebj.org