Impaired inflammatory response to glial cell death in genetically metallothionein-I- and -II-deficient mice.
Metallothionein I+II (MT-I+II) are acute-phase proteins which are upregulated during pathological conditions in the brain. To elucidate the neuropathological importance of MT-I+II, we have examined MT-I+II-deficient mice following ip injection with 6-aminonicotinamide (6-AN). 6-AN is antimetabolic and toxic for bone marrow cells and grey matter astrocytes. In MT+/+ mice, injection with 6-AN resulted in breakdown of the blood-brain barrier (BBB) and absence of GFAP-positive astrocytes in specific grey matter areas of the brain stem. Reactive astrocytosis encircled the damaged grey matter areas, which were heavily infiltrated by microglia/macrophages. The recruitment of hematogenous macrophages was accompanied by leakage of the BBB. The immunoreactivity (ir) of granulocyte-macrophage-colony-stimulating factor (GM-CSF) and the receptor for GM-CSF (GM-CSFrec) was significantly upregulated in astrocytes and microglia/macrophages, respectively. MT-I+IIir was also clearly increased in astrocytes surrounding the damaged areas, while that of the CNS-specific MT isoform, MT-III, was mildly increased in both astrocytes and microglia/macrophages. In MT-/- mice injected with 6-AN, the BBB remained almost intact. The damage to specific grey matter areas was similar to that observed in MT+/+ mice, but reactive astrocytosis, microglia/macrophages infiltration, and GM-CSFir and GM-CSFrecir were clearly reduced in MT-/- mice. In contrast, MT-IIIir was dramatically increased in MT-/- mice. Total zinc decreased and histochemically detectable zinc increased in the brain stem after 6-AN similarly in MT+/+ and MT-/- mice. Bone marrow myeloid monocytes and macrophages were increased as a reaction to 6-AN only in MT+/+ mice. The results demonstrate that the capability of MT-/- mice to mount a normal inflammatory response in the brain is severely attenuated, at least in part because of 6-AN-induced bone marrow affectation, involving MT-I+II for the first time as major factors during CNS tissue damage.
Penkowa
M
M
Institute of Medical Anatomy, Section C, The Panum Institute, Copenhagen, DK-2200, Denmark.
Giralt
M
M
Moos
T
T
Thomsen
P S
PS
Hernández
J
J
Hidalgo
J
J
D015120:6-Aminonicotinamide / Q000633:toxicity; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier; D001854:Bone Marrow Cells / Q000378:metabolism; D016923:Cell Death; D004396:Coloring Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D037102:Lectins; D008264:Macrophages / Q000378:metabolism; D008668:Metallothionein / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009525:Niacin / Q000037:antagonists & inhibitors; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D015032:Zinc / Q000378:metabolism
D004396:Coloring Agents; D037102:Lectins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D009525:Niacin; D015120:6-Aminonicotinamide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008668:Metallothionein; D015032:Zinc