CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves

Abstract

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1G93A transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1G93A mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1G93A mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease.

Pharmacological inhibition of CSF1R by GW2580 reduces microglial proliferation and is protective against neuroinflammation and dopaminergic neurodegeneration

“…[17][18][19] Here, we provide novel evidence that CSF1R signaling may likewise contribute to microglial proliferation and neuroinflammation in PD, as evidenced by increased levels of the ligand CSF-1 in postmortem PD patients, along with increased mRNA and protein levels of CSF1R, CSF-1, and IL-34 in animal models of PD. [17][18][19] Here, we provide novel evidence that CSF1R signaling may likewise contribute to microglial proliferation and neuroinflammation in PD, as evidenced by increased levels of the ligand CSF-1 in postmortem PD patients, along with increased mRNA and protein levels of CSF1R, CSF-1, and IL-34 in animal models of PD.…”

“…49 Class III receptor tyrosine kinases, which includes CSF1R, c-kit, PDGFRβ, and FLT3, all regulate cell survival through downstream pathways such as PI3K and Akt. [17][18][19] GW2580 completely blocked the MPTP-induced gene expression of Iba1 in the mouse striatum, along with significant reduction of Iba1 + and Ki-67 + / Iba1 + cells in the SN (Figure 4). 21,50,51 Recent research found that complete ablation of microglia in the brain using PLX-3397 exacerbated MPTPinduced neuroinflammation, neurotoxicity, and behavioral effects.…”

“…58 We found significant loss of the TH + and Nissl + neurons in the SN of mice treated with acute MPTP ( Figure 6C,D), demonstrating neuronal cell death and not loss of TH expression. [17][18][19] The neuroprotection is most likely through the reduction of microglial proliferation and inflammatory response; however, CSF1R has also been found in neurons. GW2580 treatment significantly abolished the MPTP-induced loss of both the TH + and Nissl + cells, along with partially rescuing MPTP-induced deficits in traversing a challenging beam and in spontaneous movements ( Figure 6E-H).…”

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…In the CNS, ALS is typically accompanied by neuroinflammation involving the emergence of reactive microglia, astrocytes, and aberrant glial phenotypes (3)(4)(5). Evidence also shows activation of circulating immune cells (6), as well as immune cell infiltration of the ALS-degenerating peripheral nerves containing motor axons (7)(8)(9)(10).…”

Focal Transplantation of Aberrant Glial Cells Carrying the SOD1^G93A Mutation into Rat Spinal Cord Induces Extensive Gliosis

“…We have previously shown that aberrant microglial cells from symptomatic ALS rats are responsive to M-CSF through the tyrosine kinase receptor CSF-1R [10]. Accordingly, the pharmacological inhibition of CSF-1R decreases microglia reactivity and extends the life span of ALS mice [10,19]. Astrocytes are another major source of M-CSF and IL-34, both factors being potent agonists of the CSF-1R [20,21].…”