CSF1R Inhibition by a Small-Molecule Inhibitor Is Not Microglia Specific; Affecting Hematopoiesis and the Function of Macrophages
This week we profile a recent publication in PNAS from the laboratory
of Dr. Eleftherios Paschalis (pictured) at Massachusetts Eye and Ear.
Can you provide a brief overview of your lab’s current research focus?
I lead a multidisciplinary laboratory integrating biology, engineering, and translational medicine to focuses in development of neuroprotective therapies and implants to restore vision. My laboratory has been on the forefront of neuroglia research since 2011, investigating the implications of microglia and peripheral monocytes on retinal neurodegeneration after trauma. Surrounded by highly motivated and innovative research fellows and collaborators, we have been early implementors of novel fate mapping techniques and in-drop single cell RNAseq technology to study the transcriptional identity of microglia and peripheral monocytes during CNS disease. To this end, we have employed microglia manipulation methods, such as PLX5622 CSF1R inhibitor, to study the dynamic remodeling of the neuroglia system in the CNS injury. Together with collaborators Prof. David Weitz and Dr. Demetrios Vavvas, we continue our quest to delineate the role and function of microglia in CNS degeneration, paving the way to new neuroprotective therapies.
What is the significance of the findings in this publication?
Colony-stimulating factor 1 receptor (CSF1R) inhibition has been extensively adopted by many laboratories for the study of microglia, with the assumption that it does not cause significant effect on peripheral immune cells. However, the specificity of CSF1R inhibition on microglia depletion has been based on rather crude assays and indirect assessment of peripheral cell subtypes and function. Given that peripheral monocytes were recently shown to participate in CNS disease via both infiltration and repopulation of neuroglia following microglia depletion, possible effects of CSF1R inhibition on the function of peripheral cells could confound the interpretation of experimental data.
In this study we show that, contrary to the accepted notion, PLX5622, a commonly used CSF1R inhibitor, does not affect only microglia but also leads to long-term changes in the myeloid and lymphoid compartments of the bone marrow, spleen, and blood, and affects the number of the tissue-resident and interstitial macrophages of the lung, liver, and peritoneum. Most importantly, these effects perdure long after cessation of the treatment. These findings are particularly important to explain previous published inconsistencies, suggesting that microglia depletion by CSF1R inhibition can either promote or exacerbate neurodegeneration; these puzzling and contradictory results may not only be due to the differing role of microglia in various disease models but also to the varying relative contribution of peripheral and circulating macrophages on disease phenotype. Thus, our work provides important information of the implications of using small-molecule inhibitor PLX5622, and these new findings need to be taken into consideration in the interpretation of relevant experimental data.
What are the next steps for this research?
Our laboratory continues its works toward a more complete understanding of the role of microglia in retinal neurodegeneration. Together with collaborators and the leading author of the current study, Dr. Fengyang Lei, we successfully completed a series of single-cell RNAseq studies in microglia and we identified a new ectopically expressed protein that plays a key role in neuroprotection. Our data will be published soon and can help in the development of new therapies for neuroprotection.
This work was funded by:
This work was funded by the Boston Keratoprosthesis fund, Massachusetts Eye and Ear.