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

Abstract

Significance Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by accumulation of myeloid cells in the central nervous system (CNS). Both harmful and beneficial myeloid cells are present in EAE/MS, and a goal of MS therapy is to preferentially remove harmful myeloid cells. The receptor for CSF-1 (CSF-1R) is found on myeloid cells and is important for their survival. CSF-1R can bind two ligands, CSF-1 and IL-34, but it is not known whether their functions in EAE/MS differ. We found that blocking CSF-1 depleted only harmful myeloid cells in the CNS and suppressed EAE, whereas blocking IL-34 had no effect. Thus, we propose that blocking CSF-1 could be a therapy for MS.

GATA1 controls numbers of hematopoietic progenitors and their response to autoimmune neuroinflammation

“…Mice were scored as described. 17 For adoptive EAE, WT and ΔdblGATA mice were immunized as described above and euthanized on days 8 to 10 after immunization. Splenocytes were restimulated with 20 μg/mL PLP 180-199 and 20 ng/mL murine recombinant interleukin 23 (IL-23) at a density of 5 × 10 7 cells per well in a 6-well tissue culture plate.…”

Augmentation of a neuroprotective myeloid state by hematopoietic cell transplantation

“…In contrast, long-term inhibition of CSF1R signaling, which is essential for microglial survival, is known to have very different effects as demonstrated in different studies investigating the contribution of CSF1 to EAE pathogenesis. [55][56][57][58][59][60] Early and continuous treatment with a CSF1R inhibitor could reduce disease severity in some studies underlining the relevance of myeloid cells in EAE pathobiology. [55][56][57][58] However, drug withdrawal led to a relapse in symptoms suggesting that no sustained modulation of the myeloid niche was achieved thus limiting translational value.…”

“…[55][56][57][58][59][60] Early and continuous treatment with a CSF1R inhibitor could reduce disease severity in some studies underlining the relevance of myeloid cells in EAE pathobiology. [55][56][57][58] However, drug withdrawal led to a relapse in symptoms suggesting that no sustained modulation of the myeloid niche was achieved thus limiting translational value. 57 These results, in light of the findings of our study, demonstrate that the role of myeloid cells is complex.…”

Inhaled Macrophage Apoptotic Bodies-Engineered Microparticle Enabling Construction of Pro-Regenerative Microenvironment to Fight Hypoxic Lung Injury in Mice

“…13 Unfortunately, these growth factors, as biologic therapeutics, are conventionally administered systemically via intravenous injection, which limits their accumulation in targeted lung tissues, leading to decreased therapeutic efficacy. 14 Furthermore, one must also be aware of the potential risk of CSF-1 treatment for systemic side effects. 15 Herein, we developed an inhalable platform that could sustainably inhibit inflammasome-mediated AEC damage while also improving CSF delivery for innate immune cell reprogramming in lung injury (Scheme 1).…”

“…In addition to alveolar damage, patients with ARDS developed profoundly monocytopenia, with a failure to expand monocyte-derived macrophages and persistent inflammation. , Recently, research efforts have confirmed the effect of monocyte and macrophage growth factor colony-stimulating factor 1 (CSF-1) on correcting these hypoxia-mediated immune changes, indicating the therapeutic benefit of CSF-1 in ARDS . Unfortunately, these growth factors, as biologic therapeutics, are conventionally administered systemically via intravenous injection, which limits their accumulation in targeted lung tissues, leading to decreased therapeutic efficacy . Furthermore, one must also be aware of the potential risk of CSF-1 treatment for systemic side effects …”