Compromised reactive microgliosis in MPTP-lesioned IL-6 KO mice.
Reactive gliosis, the cellular manifestation of neuroinflammation, is a pathological hallmark of neurodegenerative diseases including Parkinson's disease. The persistent gliosis observed in the Parkinson's disease substantia nigra (SN) and in humans and animals exposed to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) may represent a chronic inflammatory response that contributes to pathology. We have previously shown that in the absence of interleukin-6 (IL-6) dopaminergic neurons are more vulnerable to MPTP. Since IL-6 is both an autocrine and paracrine proliferation factor for CNS glia, we investigated reactive gliosis in MPTP-lesioned IL-6 (-/-) mice. While astrogliosis was similar in injured IL-6 (+/+) and IL-6 (-/-) SN pars compacta (pc), microgliosis was severely compromised in IL-6 (-/-) mice. In the absence of IL-6, an acute reactive microgliosis was transient with a complete absence of reactive microglia at day 7 post-lesion. Extensive reactive microgliosis was observed in the SNpc of MPTP-lesioned IL-6 (+/+) mice. Because glial derived inducible nitric oxide synthase (iNOS) has been implicated in dopaminergic cell death, we examined glial iNOS expression in the IL-6 genotypes to determine if it correlated with the greater vulnerability and reduced microgliosis observed in the MPTP-lesioned IL-6 (-/-) nigrostriatal system. Both reactive microglia and astrocytes expressed iNOS in the lesioned SNpc. In the IL-6 (-/-) mice, microglial iNOS expression diminished as reactive microgliosis declined. The data suggest IL-6 regulation of microglia activation, while iNOS expression appears to be secondary to cell activation.
Cardenas
Hernan
H
The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089, USA.
Bolin
Laurel M
LM
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D005911:Gliosis / Q000235:genetics / Q000473:pathology*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology*; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*
D015850:Interleukin-6; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse