Investigation of inflammation in the mouse skull and the whole body
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2019-08-15
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en
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Stroke pathophysiology effects the whole body, is highly complex and consists of an acute stage followed by a chronic stage. Recent findings have shifted from investigating neuroprotective agents to understanding the neuroinflammatory response stroke has, which was shown to play an important role in its progression with contradictory roles: ranging from beneficial to damaging. In regards to this response, peripheral immune infiltration has been appointed an important player via the partly established invasion routes. In conjunction with this, our group has discovered a new putative route for peripheral immune cells to invade the brain. This route, namely the skull-meninges connections (SMCs) connect the skull bone marrow into the meninges and enable myeloid cell trafficking. In the present study, the aim was to investigate the unique role of the skull bone marrow and the SMCs in stroke pathobiology in comparison to other bone marrows in the body. To this extent, we induced stroke in BL6 and LySM-eGFP mice (expressed in monocytes, neutrophils and macrophages) by middle cerebral artery occlusion (MCAO) model of stroke. After assessing their behavioral deficits such as their locomotion and balance, we applied tissue clearing and imaging on the whole mouse to identify LysM signal changes in the skull in comparison to other bones such as the scapula, the femur etc. after stroke. Additonally, single cell RNA sequencing and mass spectrometry experiments examined transcriptome and proteome differences among the samples. The results from imaging showed that the immune cells expressing GFP were found in the SMCs up to six weeks after MCAO operation and MCAO operated animals showed relatively higher immune cell signal compared to sham operated animals. The total signal was almost equal in acute and chronic stages of stroke for MCAO-operated and sham-operated animals. Moreover, we identified a negative trend between the immune cell signal from the skull bone marrow cavities and the behavioral deficits, indicating an association between the skull’s response and behavior that could be used as a biomarker in the future. The results from the –omics data supported the hypothesis that the cell identities are different in the skull compared to the femur bone; we identified more than 200 hundred proteins that were differentially expressed among the samples. Lastly, we observed that distal bones to the injury appears to be depleted with immune cells unlike the increase we observe in the skull, underlining the unique response of the skull. In sum, we showed that stroke induces consecutive changes not only in the brain but also in the whole body. The skull emerged as a player in this pathobiology that will be further investigated.
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Faculteit der Sociale Wetenschappen