CSF-1 Maintains Pathogenic but Not Homeostatic Myeloid Cells in the Central Nervous System During Autoimmune Neuroinflammation
Abstract
Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are autoimmune diseases of the central nervous system (CNS) characterized by accumulation of immune cells in the CNS which eventually form demyelinated lesions. Multiple types of immune cells are found in MS lesions, but myeloid cells predominate, comprising up to 78% of all immune cells. Myeloid cells are prime candidates for targeting in therapy, but no MS therapies currently exist that directly and specifically target myeloid cells. Of particular interest for MS therapy has been targeting colony-stimulating factors, a small family of proteins that crucially impact multiple facets of myeloid cell biology. The receptor for colony stimulating factor-1 (CSF-1R) is a cell surface receptor tyrosine kinase required for survival of multiple myeloid cell types (e.g. monocytes, microglia). CSF-1R has been targeted in EAE, but existing studies have shown highly variable therapeutic efficacy, most likely due to pleiotropic effects caused by global inhibition of CSF-1R signaling. Direct targeting of CSF-1R also has the potential drawback of profound and unnecessary depletion of non-pathogenic myeloid cells, such as homeostatic microglia and Langerhans cells. We reasoned that instead of targeting CSF1R itself, selective depletion of inflammatory myeloid cells could be achieved via targeting its ligands, CSF-1 and IL-34, which have similar bioactivity but context dependent differences in expression, including in EAE, where CSF-1 expression is upregulated in the CNS, while IL-34 remains constitutively expressed. We compared the effects of blocking CSF-1R with small molecule inhibitor, and CSF-1 and IL-34 with neutralizing mAbs. We found that blocking CSF-1R or CSF-1 markedly suppresses clinical disease in EAE, whereas blocking IL-34 had no effect. However, targeting CSF-1 was superior to targeting CSF-1R in several notable and important aspects. In contrast to targeting CSF-1R, which depleted virtually all microglia, targeting CSF-1 preferentially depleted inflammatory myeloid cells in lesions, while sparing microglia in the rest of the CNS. In addition, neutralization of CSF-1 precluded widespread activation of microglia in normal appearing white and grey matter, thus indicating a reduction in overall CNS inflammation. In long-term therapeutic treatments, blocking CSF-1 continuously suppressed disease, whereas blocking CSF-1R suppressed disease only transiently. We therefore propose that neutralization of CSF-1 could be a novel therapeutic strategy for MS that minimizes the risks associated with total ablation of CSF-1R signaling.
Subject Area
Immunology|Cellular biology|Epidemiology
Recommended Citation
Hwang, Daniel, "CSF-1 Maintains Pathogenic but Not Homeostatic Myeloid Cells in the Central Nervous System During Autoimmune Neuroinflammation" (2023). ProQuest ETD Collection - Thomas Jefferson University. AAI30425181.
https://jdc.jefferson.edu/dissertations/AAI30425181
