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Emerging evidence highlights exosomes as vital mediators of mast cell\u2013neuron interactions in neurological disease progression. While mast cells and their exosomes were previously shown to exacerbate experimental cerebral malaria (ECM) severity, the specific role of mast cell-derived exosomes in CM-associated neuronal injury remains unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Exosomes were isolated from resting and lipopolysaccharide (LPS)-activated P815 mast cells (denoted as <jats:italic>RE<\/jats:italic> and <jats:italic>AE<\/jats:italic>, respectively) and characterized. These exosomes were administered to ECM mice and <jats:italic>Plasmodium berghei<\/jats:italic> ANKA (<jats:italic>Pb<\/jats:italic>A)-infected red blood cell (iRBC)-stimulated neuronal HT-22 cells to investigate their functional impact and mechanisms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Both <jats:italic>RE<\/jats:italic> and <jats:italic>AE<\/jats:italic> exhibited spherical morphology (20\u2013100\u00a0nm diameter) and expressed exosomal markers (CD9, CD63, and CD81). Compared to infected controls, <jats:italic>RE<\/jats:italic> and <jats:italic>AE<\/jats:italic> treatments significantly reduced survival time, increased ECM incidence, and exacerbated brain pathology, blood\u2013brain barrier disruption, neuronal injury, and apoptosis. Furthermore, <jats:italic>RE<\/jats:italic> and <jats:italic>AE<\/jats:italic> administration elevated messenger RNA (mRNA) levels of pro-inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor alpha [TNF-\u03b1], and IL-1\u03b2) and increased numbers of neurons expressing endoplasmic reticulum (ER) stress markers (GRP78, CHOP, p-IRE1, XBP-1). Notably, <jats:italic>AE<\/jats:italic> treatment induced higher morbidity\/mortality rates, more severe neuronal injury, and greater ER stress marker expression than <jats:italic>RE<\/jats:italic>. In vitro, <jats:italic>RE<\/jats:italic>-treated iRBC-stimulated neuronal HT-22 cells showed higher GRP78, CHOP, and XBP-1 mRNA levels than <jats:italic>AE<\/jats:italic>-treated cells. MicroRNA (miRNA) sequencing revealed three downregulated miRNAs (miR-330-3p, miR-185-5p, and miR-379-5p) and six upregulated miRNAs (miR-155-5p, miR-423-3p, miR-187-3p, miR-29c-3p, miR-188-5p, miR-192-5p) in <jats:italic>AE<\/jats:italic> versus <jats:italic>RE<\/jats:italic>, all previously implicated in targeting GRP78, CHOP, or XBP-1.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Mast cell-derived exosomes, particularly those from activated cells (<jats:italic>AE<\/jats:italic>), exacerbated ECM neuronal injury through partial activation of ER stress pathways.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1186\/s13071-025-06863-3","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T13:34:00Z","timestamp":1751376840000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of mast cell-derived exosomes in exacerbating neuronal injury of experimental cerebral malaria"],"prefix":"10.1186","volume":"18","author":[{"given":"Qianru","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiumei","family":"Mo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingqiu","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guojun","family":"Fei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pinru","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinpeng","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiajing","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenbin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zujun","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobao","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenlong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"6863_CR1","volume-title":"World malaria report 2023","author":"WHO","year":"2023","unstructured":"WHO. 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