Systemic inflammation switches the inflammatory cytokine profile in CNS Wallerian degeneration.
Axon loss in the CNS is characteristic of many neurodegenerative diseases but the mechanisms of axon degeneration are poorly understood. In particular, we know little of the inflammatory response triggered by CNS axon degeneration with comparison to that provoked by death of the neuronal cell body. We show that Wallerian degeneration of the mouse optic nerve induces transcription of TGF-beta1 and TNF-alpha, but not pro-inflammatory cytokines IL-1beta and IL-6 and microglial activation. This atypical inflammatory response resembles macrophages that have phagocytosed apoptotic cells and prion-infected CNS. Significantly, peripheral endotoxin challenge after injury switched this profile by inducing IL-1beta, IL-6 transcripts, other inflammation-associated products and reducing neurofilament immunoreactivity. We propose that microglia are activated by Wallerian degeneration and persist in an atypical but "primed" state and can be switched by systemic inflammation to provoke a classical pro-inflammatory profile with potentially deleterious consequences.
Palin
Karine
K
CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK.
Cunningham
Colm
C
Forse
Penny
P
Perry
V Hugh
VH
Platt
Nick
N
D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D011134:Polysaccharides / Q000008:administration & dosage; D000683:Serum Amyloid P-Component / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014855:Wallerian Degeneration / Q000473:pathology*; D000099153:Pentraxins; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002097:C-Reactive Protein; D051546:Cyclooxygenase 2; D016207:Cytokines; D052247:Nitric Oxide Synthase Type II; D017395:Plasminogen Activator Inhibitor 1; D011134:Polysaccharides; D000683:Serum Amyloid P-Component; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000099153:Pentraxins; C067980:CD68 antigen, human; D000097382:CD68 Molecule