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Microglial mitogens are produced in the developing and injured mammalian brain
D Giulian1, B Johnson, J F Krebs
1Department of Neurology, Baylor College of Medicine, Houston, Texas 77030.
Abstract:
The central nervous system produces growth factors that stimulate proliferation of ameboid microglia during embryogenesis and after traumatic injury. Two microglial mitogens (MMs) are recovered from the brain of newborn rat. MM1 has an approximate molecular mass of 50 kD and a pI of approximately 6.8; MM2 has a molecular mass of 22 kD and a pI of approximately 5.2. These trypsin-sensitive proteins show specificity of action upon glia in vitro serving as growth factors for ameboid microglia but not astroglia or oligodendroglia. Although the MMs did not stimulate proliferation of blood monocytes or resident peritoneal macrophage, MM1 shows granulocyte macrophage colony-stimulating activity when tested upon bone marrow progenitor cells. Microglial mitogens may help to control brain mononuclear phagocytes in vivo. The MMs first appear in the cerebral cortex of rat during early development with peak levels around embryonic day E-20, a period of microglial proliferation. Microglial mitogens are also produced by traumatized brain of adult rats within 2 d after injury. When infused into the cerebral cortex, MM1 and MM2 elicit large numbers of mononuclear phagocytes at the site of injection. In vitro study shows that astroglia from newborn brain secrete MM2. These observations point to the existence of a regulatory system whereby secretion of proteins from brain glia helps to control neighboring inflammatory responses.
Insights
Two brain-derived microglial mitogens (MMs) stimulate microglia growth during development and injury. These proteins, MM1 and MM2, regulate brain mononuclear phagocytes and inflammatory responses.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- The central nervous system (CNS) produces growth factors influencing microglial proliferation during development and after injury.
- Microglia, the resident immune cells of the CNS, play critical roles in brain homeostasis and disease.
- Understanding the regulation of microglial populations is crucial for addressing neurological disorders.
Purpose of the Study:
- To identify and characterize growth factors that stimulate ameboid microglia proliferation in the developing and injured brain.
- To investigate the specificities and functions of these microglial mitogens (MMs) in vitro and in vivo.
- To elucidate the role of brain glia in producing and regulating microglial responses.
Main Methods:
- Biochemical purification and characterization of microglial mitogens (MMs) from newborn rat brain.
- In vitro proliferation assays using primary glial cultures (microglia, astroglia, oligodendroglia) and bone marrow progenitor cells.
- In vivo studies involving infusion of MMs into the rat cerebral cortex to assess inflammatory cell recruitment.
Main Results:
- Two distinct microglial mitogens, MM1 (50 kD, pI 6.8) and MM2 (22 kD, pI 5.2), were isolated and characterized.
- MMs specifically promoted the proliferation of ameboid microglia in vitro, without affecting astroglia or oligodendroglia.
- MM1 demonstrated granulocyte-macrophage colony-stimulating activity, while MMs did not stimulate blood monocytes or macrophages.
- MMs were detected during embryonic development (peak at E-20) and after traumatic brain injury, with astroglia identified as a source of MM2.
- In vivo administration of MMs led to significant recruitment of mononuclear phagocytes to the injection site.
Conclusions:
- Brain-derived microglial mitogens (MMs) are key regulators of microglial proliferation during development and in response to injury.
- These MMs represent a specific signaling system controlling CNS mononuclear phagocyte populations.
- Secretion of MMs by brain glia suggests an intrinsic regulatory mechanism for managing local inflammatory responses within the CNS.