CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 14; p. e2111804119
• Main Authors: Hwang, Daniel, Seyedsadr, Maryam S, Ishikawa, Larissa Lumi Watanabe, Boehm, Alexandra, Sahin, Ziver, Casella, Giacomo, Jang, Soohwa, Gonzalez, Michael V, Garifallou, James P, Hakonarson, Hakon, Zhang, Weifeng, Xiao, Dan, Rostami, Abdolmohamad, Zhang, Guang-Xian, Ciric, Bogoljub
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.04.2022
• Subjects: Ablation; Animal models; Animals; Antibodies; Benzothiazoles - pharmacology; Benzothiazoles - therapeutic use; Biological Sciences; Bone marrow; Central nervous system; Central Nervous System - immunology; Cerebrospinal fluid; Colony-stimulating factor; Depletion; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Experimental allergic encephalomyelitis; Immune system; Inflammation; Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Macrophage Colony-Stimulating Factor - metabolism; Mice; Mice, Inbred C57BL; Microglia; Monocytes; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Myeloid cells; Myeloid Cells - drug effects; Myeloid Cells - metabolism; Neutralization; Pathology; Picolinic Acids - pharmacology; Picolinic Acids - therapeutic use; Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Substantia grisea; EAE; CSF-1; IL-34; multiple sclerosis; CSF-1R
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2111804119

The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bioactivities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is up-regulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing antibody halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1. Both anti–CSF-1 and BLZ945 treatment greatly reduced the number of monocyte-derived cells and microglia in the CNS. However, anti–CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti–CSF-1 treatment reduced the size of demyelinated lesions and microglial activation in the gray matter. Lastly, we found that bone marrow–derived immune cells were the major mediators of CSF-1R–dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with ablation of CSF-1R–dependent cells.