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Genetically induced brain inflammation by Cnp deletion transiently benefits from microglia depletion
Author(s) -
Garcia-Agudo Laura Fernandez,
Janova Hana,
Sendler Lea E.,
Arinrad Sahab,
Steixner Agnes A.,
Hassouna Imam,
Balmuth Evan,
Ronnenberg Anja,
Schopf Nadine,
Flier Felicia J.,
Begemann Martin,
Martens Henrik,
Weber Martin S.,
Boretius Susann,
Nave Klaus-Armin,
Ehrenreich And Hannelore
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201900337r
Subject(s) - microglia , inflammation , neuroscience , microbiology and biotechnology , biology , immunology
Reduced expression of 2′‐3′‐cyclic nucleotide 3′‐phosphodiesterase ( Cnp ) in humans and mice causes white matter inflammation and catatonic signs. These consequences are experimentally alleviated by microglia ablation via colony‐stimulating factor 1 receptor (CSF1R) inhibition using PLX5622. Here we address for the first time preclinical topics crucial for translation, most importantly 1 ) the comparison of 2 long‐term PLX5622 applications (prevention and treatment) vs . 1 treatment alone, 2) the correlation of catatonic signs and executive dysfunction, 3) the phenotype of leftover microglia evading depletion, and 4) the role of intercellular interactions for efficient CSF1R inhibition. Based on our Cnp –/– mouse model and in vitro time‐lapse imaging, we report the unexpected discovery that microglia surviving under PLX5622 display a highly inflammatory phenotype including aggressive premortal phagocytosis of oligodendrocyte precursor cells. Interestingly, ablating microglia in vitro requires mixed glial cultures, whereas cultured pure microglia withstand PLX5622 application. Importantly, 2 extended rounds of CSF1R inhibition are not superior to 1 treatment regarding any readout investigated (magnetic resonance imaging and magnetic resonance spectroscopy, behavior, immunohistochemistry). Catatonia‐related executive dysfunction and brain atrophy of Cnp –/– mice fail to improve under PLX5622. To conclude, even though microglia depletion is temporarily beneficial and worth pursuing, complementary treatment strategies are needed for full and lasting recovery.—Fernandez Garcia‐Agudo, L., Janova, H., Sendler, L. E., Arinrad, S., Steixner, A. A., Hassouna, I., Balmuth, E., Ronnenberg, A., Schopf, N., van der Flier, F. J., Begemann, M., Martens, H., Weber, M. S., Boretius, S., Nave, K.‐A., Ehrenreich, H. Genetically induced brain inflammation by Cnp deletion transiently benefits from microglia depletion. FASEB J. 33, 8634–8647 (2019). www.fasebj.org