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Widespread expression of MRP8 and MRP14 in human cerebral malaria by microglial cells
H J Schluesener1, P G Kremsner, R Meyermann
1Institute of Brain Research, University of Tübingen, Germany.
Abstract:
Human cerebral malaria (CM) is an often fatal infection. The cascades of signaling events resulting in tissue trauma and coma are only slowly becoming unraveled. Here we report that microglial cells--sensitive cellular sensors of threats to the central nervous system--in CM express the myeloid-related proteins MRP8 (S100A8) and MRP14 (S100A9), Ca2+-binding sensor proteins of activated monocytes. Surprisingly, microglial activation was widespread throughout the brain in white and gray matter and not limited to areas of petechial bleedings or sequestration of infected erythrocytes. Further, apoptosis/necrosis is prominent in CM; not only leukocytes appeared apoptotic, neurons also appeared damaged and DNA fragmentation was revealed by in situ nick translation. Thus, a prominent feature of human CM is activation of microglia, and analysis of these reactive microglia might further promote our understanding of CM pathology and guide development of future therapeutic intervention of the local reactive processes.
Insights
Human cerebral malaria (CM) involves widespread microglial activation, indicated by myeloid-related proteins MRP8/MRP14. This widespread brain inflammation and neuronal damage in CM offers new therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Human cerebral malaria (CM) is a severe, often fatal neurological complication of Plasmodium falciparum infection.
- The precise cellular and molecular mechanisms driving CM pathogenesis, including brain injury and coma, remain incompletely understood.
- Microglial cells are key immune sentinels within the central nervous system (CNS).
Purpose of the Study:
- To investigate the role and activation status of microglial cells in human cerebral malaria.
- To identify specific molecular markers expressed by activated microglia in CM brains.
- To correlate microglial activation with neuropathological changes observed in CM.
Main Methods:
- Immunohistochemical analysis of post-mortem brain tissue from human CM patients.
- Detection of myeloid-related proteins MRP8 (S100A8) and MRP14 (S100A9) in microglial cells.
- Assessment of apoptosis/necrosis and DNA fragmentation in neural and immune cells using in situ nick translation.
Main Results:
- Microglial cells in CM brains express myeloid-related proteins MRP8 and MRP14, indicative of activation.
- Microglial activation was observed throughout both white and gray matter, not confined to areas of vascular pathology.
- Significant apoptosis/necrosis was evident in leukocytes and neurons, with widespread DNA fragmentation.
Conclusions:
- Widespread microglial activation is a prominent feature of human cerebral malaria.
- The expression of MRP8/MRP14 by reactive microglia provides a marker for CNS immune response in CM.
- Understanding these reactive microglial processes is crucial for developing targeted therapies for CM.