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 upregulat ed during pathological conditions in the brain. To elucidate the neuropatho logical importance of MT-I+II, we have examined MT-I+II-deficient mice foll owing ip injection with 6-aminonicotinamide (6-AN). 6-AN is antimetabolic a nd toxic for bone marrow cells and grey matter astrocytes, In MT+/+ mice, i njection with 6-AN resulted in breakdown of the blood-brain barrier (BBB) a nd 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 o f hematogenous macrophages was accompanied by leakage of the BBB. The immun oreactivity (ir) of granulocyte-macrophage-colony-stimulating factor (GM-CS F) and the receptor for GM-CSF (GM-CSFrec) was significantly upregulated in astrocytes and microglia/macrophages, respectively, MT-I+IIir was also cle arly increased in astrocytes surrounding the damaged areas, while that of t he CNS-specific MT isoform, MT-III, was mildly increased in both astrocytes and microglial macrophages. In MT-/- mice injected with 6-AN, the BBB rema ined almost intact. The damage to specific grey matter areas was similar to that observed in MT+/+ mice, but reactive astrocytosis, microglia/ macroph ages infiltration, and GM-CSFir and GM-CSFrecir were clearly reduced in MT- /- mice. In contrast,MT-IIIir was dramatically increased in MT-/- mice. Tot al zinc decreased and histochemically detect able zinc increased in the bra in stem after 6-AN similarly in MT+/+ and MT-/- mice. Bone marrow myeloid m onocytes 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, (C) 1999 Aca demic Press.