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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 SOD1(G93A) transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1(G93A) 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 SOD1(G93A) 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.

SUBMITTER: Martinez-Muriana A

PROVIDER: S-EPMC4865981 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Project description:ImportanceAmyotrophic lateral sclerosis (ALS) has an immune component, but previous human studies have not examined immune changes over time.ObjectivesTo assess peripheral inflammatory markers in participants with ALS and healthy control individuals and to track immune changes in ALS and determine whether these changes correlate with disease progression.Design, setting, and participantsIn this longitudinal cohort study, leukocytes were isolated from peripheral blood samples from 35 controls and 119 participants with ALS at the ALS Clinic of the University of Michigan, Ann Arbor, from June 18, 2014, through May 26, 2016. Follow-up visits occurred every 6 to 12 months. Fifty-one participants with ALS provided samples at multiple points. Immune cell populations were measured and compared between control and ALS groups. Surface marker expression of CD11b+ myeloid cells was also assessed. Changes over time were correlated with disease progression using multivariate regression.Main outcomes and measuresThe number of immune cells per milliliter of blood and the fold expression of cell surface markers. Multivariate regression models were used to correlate changes in immune metrics with changes on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).ResultsThirty-five controls (17 women [48.6%] and 18 men [51.4%]; mean [SD] age, 63.5 [9.9] years) and 119 participants with ALS (50 women [42.0%] and 69 men [68.0%]; mean [SD] age, 61.4 [11.5] years) were enrolled. Compared with controls, participants with ALS had increased mean (SEM) counts (?×?106/mL) of total leukocytes (4.57 [0.29; 95% CI, 3.94-5.11] vs 5.53 [0.16; 95% CI, 5.21-5.84]), neutrophils (2.87 [0.23; 95% CI, 2.40-3.35] vs 3.80 [0.12; 95% CI, 3.56-4.04]), CD16+ monocytes (0.03 [0.003; 95% CI, 0.02-0.04] vs 0.04 [0.002; 95% CI, 0.03-0.04]), CD16- monocytes (0.25 [0.02; 95% CI, 0.21-0.30] vs 0.29 [0.01; 95% CI, 0.27-0.31]), and natural killer cells (0.13 [0.02; 95% CI, 0.10-0.17] vs 0.18 [0.01; 95% CI, 0.16-0.21]). We also observed an acute, transient increase in a population of CD11b+ myeloid cells expressing HLA-DR, CD11c, and CX3CR1. Finally, early changes in immune cell numbers had a significant correlation with disease progression measured by change in ALSFRS-R score, particularly neutrophils (-4.37 [95% CI, -6.60 to -2.14] per 11.47?×?104/mL [SD, 58.04?×?104/mL] per year) and CD4 T cells (-30.47 [95% CI, -46.02 to -14.94] per -3.72?×?104/mL [SD, 26.21?×?104/mL] per year).Conclusions and relevanceChanges in the immune system occur during ALS and may contribute to the pathologic features of ALS.

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

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