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Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling.

Cell reports (2020-03-05)
Violeta Chitu, Fabrizio Biundo, Gabriel G L Shlager, Eun S Park, Ping Wang, Maria E Gulinello, Şölen Gokhan, Harmony C Ketchum, Kusumika Saha, Michael A DeTure, Dennis W Dickson, Zbignew K Wszolek, Deyou Zheng, Andrew L Croxford, Burkhard Becher, Daqian Sun, Mark F Mehler, E Richard Stanley
ABSTRAKT

CSF-1R haploinsufficiency causes adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Previous studies in the Csf1r+/- mouse model of ALSP hypothesized a central role of elevated cerebral Csf2 expression. Here, we show that monoallelic deletion of Csf2 rescues most behavioral deficits and histopathological changes in Csf1r+/- mice by preventing microgliosis and eliminating most microglial transcriptomic alterations, including those indicative of oxidative stress and demyelination. We also show elevation of Csf2 transcripts and of several CSF-2 downstream targets in the brains of ALSP patients, demonstrating that the mechanisms identified in the mouse model are functional in humans. Our data provide insights into the mechanisms underlying ALSP. Because increased CSF2 levels and decreased microglial Csf1r expression have also been reported in Alzheimer's disease and multiple sclerosis, we suggest that the unbalanced CSF-1R/CSF-2 signaling we describe in the present study may contribute to the pathogenesis of other neurodegenerative conditions.

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Sigma-Aldrich
Triton X-100, laboratory grade
Sigma-Aldrich
Adenosine 5′-diphosphoribose sodium salt, ≥93%
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Celite® 545, filter aid, treated with sodium carbonate, flux calcined
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Anti-Poly ADP-ribose Antibody, clone 10H, clone 10H, from mouse