Biology subjects

Shirakawa, H.

Publications and source records attributed to Shirakawa, H..

3 recordsLinked to original sources

bioRxiv2024

Lysophosphatidic acid receptor 1 influences disease severity in a mouse model of multiple sclerosis

Multiple sclerosis (MS), a chronic inflammatory disease affecting the central nervous system (CNS), is characterized by demyelination and axonal degeneration. Current treatments, which focus mainly on reducing lymphocyte infiltration into the CNS, are insufficient due to serious side effects and limited effectiveness; thus, identifying drugs with new mechanisms of action is crucial. Lysophosphatidic acid (LPA), a bioactive lipid produced by the enzyme autotaxin, may play a role in MS pathogenesis. Specifically, the LPA1 subtype of LPA receptors is linked to release of inflammatory cytokines in the CNS, and to demyelination in the peripheral nervous system. Our study investigated the role of LPA1 in a mouse model of MS. Knocking out the LPA1 gene in mice with experimental autoimmune encephalomyelitis improved clinical outcomes and reduced demyelination. Additionally, the absence of LPA1 reduced activation of Iba1-positive cells. Treatment with AM095, an LPA1 antagonist, tended to improve clinical outcomes and reduce levels of inflammatory mediators. These findings indicate that activation of LPA1 contributes to MS pathogenesis by promoting microglial activation and infiltration of peripheral immune cells.

neuroscience↗

bioRxiv2024

Oligodendrocyte precursor cells exacerbate acute CNS inflammation via macrophage and T cell activation in a mouse model of multiple sclerosis

Oligodendrocyte precursor cells (OPCs) are a type of glial cell that differentiates into mature oligodendrocytes, a cell type that contributes to myelination, but their roles in the pathologies are not fully understood. Activities other than differentiation into oligodendrocytes have recently been reported for OPCs present in the inflammatory milieu, but intervention studies using animal models are lacking. This study aimed to explore the role of OPCs in mouse MS model experimental autoimmune encephalomyelitis (EAE). Using inducible diphtheria toxin receptor-expressing transgenic mice, platelet-derived growth factor receptor A (PDGFR)+ OPCs were depleted in EAE mice. Surprisingly, OPC depletion in the acute phase improved clinical scores and reduced demyelination. Major histocompatibility complex (MHC) class II was reduced in the spinal cord, whereas astrocyte marker and blood-spinal cord barrier tight junction and adhesion molecule expressions were unaffected after OPC depletion. The numbers of T cells and IL17-expressing Th17 cells were decreased in the spinal cords of the OPC-depleted group. MHC class II expression in spinal cord macrophages was consistently decreased by OPC depletion. These data suggest that in the acute phase of EAE, OPCs are involved in activation of infiltrated macrophages and induce subsequent T cell activation and neuroinflammation. Although the precise mechanisms remain unclear, this implies that OPCs exist not only as the source for oligodendrocytes but also play a pivotal role in central nervous system (CNS) autoimmune inflammation. Table of Contents Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/596190v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@98162dorg.highwire.dtl.DTLVardef@d7f92dorg.highwire.dtl.DTLVardef@1280619org.highwire.dtl.DTLVardef@a85907_HPS_FORMAT_FIGEXP M_FIG C_FIG MAIN POINTSO_LIOPC depletion in the acute phase of EAE improved clinical scores and reduced demyelination. C_LIO_LIOPC depletion in the spinal cord suppressed Antigen presentation via MHC class II. C_LIO_LIOPCs are involved in activation of infiltrated macrophages and induce subsequent T cell activation and neuroinflammation. C_LI

neuroscience↗

bioRxiv2024

Transcriptional landscape of the dorsal raphe serotonin neurons rendering stress resiliency

Major depressive disorder (MDD) is a serious and large social problem, yet the pathophysiology of MDD and the action mechanism of antidepressants are still poorly understood. A number of studies have reported that activation and inactivation of serotonin neurons in the dorsal raphe nucleus (DRN) cause antidepressant-like effects and depressive-like behaviors, respectively. Also, their physiological neural activities are increased when mice were chronically administered an SSRI and decreased in mice exposed to chronic social defeat stress (CSDS), a mouse model of depression. However, the molecular mechanism underlying these neural activity changes in DRN serotonin neurons remains unclear. In this study, we performed a DRN serotonin neuron-specific comprehensive gene expression analysis by using Translating Ribosome Affinity Purification (TRAP) technology in both chronic SSRI-treated mice as a model of antidepressant treatment and CSDS mice as a model of depression. It revealed that many gene expression changes were the opposite between SSRI-treated mice and CSDS-susceptible mice. Among these, we identified S100a10 as a prodepressive gene in DRN serotonin neurons, and we found that Interleukin-4 (IL-4) - Signal Transducer and Activator of Transcription 6 (STAT6) pathway and 5-HT1B receptor were the upstream and downstream molecules of S100a10, respectively. Our findings provide insights into molecular mechanisms underlying the action of antidepressants and stress resiliency.

pharmacology and toxicology↗