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Targeting the CD146/Galectin-9 axis protects the integrity of the blood-brain barrier in experimental cerebral
Hongxia Duan1, Shuai Zhao2, Jianquan Xiang2,3
1Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. cherryshoen@ibp.ac.cn.
Abstract:
Cerebral malaria (CM) is a life-threatening diffuse encephalopathy caused by Plasmodium falciparum, in which the destruction of the blood-brain barrier (BBB) is the main cause of death. However, increasing evidence has shown that antimalarial drugs, the current treatment for CM, do little to protect against CM-induced BBB damage. Therefore, a means to alleviate BBB dysfunction would be a promising adjuvant therapy for CM. The adhesion molecule CD146 has been reported to be expressed in both endothelial cells and proinflammatory immune cells and mediates neuroinflammation. Here, we demonstrate that CD146 expressed on BBB endothelial cells but not immune cells is a novel therapeutic target in a mouse model of experimental cerebral malaria (eCM). Endothelial CD146 is upregulated during eCM development and facilitates the sequestration of infected red blood cells (RBCs) and/or proinflammatory lymphocytes in CNS blood vessels, thereby promoting the disruption of BBB integrity. Mechanistic studies showed that the interaction of CD146 and Galectin-9 contributes to the aggregation of infected RBCs and lymphocytes. Deletion of endothelial CD146 or treatment with the anti-CD146 antibody AA98 prevents severe signs of eCM, such as limb paralysis, brain vascular leakage, and death. In addition, AA98 combined with the antiparasitic drug artemether improved the cognition and memory of mice with eCM. Taken together, our findings suggest that endothelial CD146 is a novel and promising target in combination with antiparasitic drugs for future CM therapies.
Insights
Targeting CD146 on brain endothelial cells offers a new therapeutic strategy for cerebral malaria (CM). Blocking CD146 with an antibody, alongside antimalarial drugs, improved outcomes in experimental CM, suggesting a promising adjuvant therapy.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, characterized by blood-brain barrier (BBB) destruction and high mortality.
- Current antimalarial drugs are insufficient in preventing CM-induced BBB damage, necessitating adjuvant therapies.
- The adhesion molecule CD146 is implicated in neuroinflammation and expressed on endothelial and immune cells.
Purpose of the Study:
- To investigate CD146 as a therapeutic target for experimental cerebral malaria (eCM).
- To determine the role of endothelial CD146 in BBB disruption during eCM.
- To evaluate the efficacy of targeting CD146 as an adjuvant therapy for CM.
Main Methods:
- Utilized a mouse model of experimental cerebral malaria (eCM).
- Investigated the expression and function of CD146 in brain endothelial cells during eCM.
- Employed genetic deletion of endothelial CD146 and administration of anti-CD146 antibody (AA98).
- Assessed the impact of anti-CD146 therapy, alone and combined with artemether, on eCM severity and cognitive function.
Main Results:
- Endothelial CD146 expression is upregulated during eCM and contributes to BBB damage.
- CD146 facilitates the adhesion of infected red blood cells and lymphocytes to CNS blood vessels.
- Targeting endothelial CD146 with antibody AA98 prevented severe eCM symptoms and mortality.
- Combination therapy with AA98 and artemether improved cognitive and memory deficits in eCM mice.
Conclusions:
- Endothelial CD146 is a critical mediator of BBB dysfunction and pathology in experimental cerebral malaria.
- Targeting endothelial CD146 represents a novel therapeutic strategy for CM.
- Combination therapy involving anti-CD146 antibodies and antiparasitic drugs shows potential for improving CM treatment outcomes.
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