CSF1R Ligands IL-34 and CSF1 Are Differentially Required for Microglia Development and Maintenance in White and Gray Matter Brain Regions

Easley-Neal, Courtney; Foreman, Oded; Sharma, Neeraj; Zarrin, Ali A.; Weimer, Robby M.

doi:10.3389/fimmu.2019.02199

Cited by 125 publications

(114 citation statements)

References 58 publications

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“…However, it proved to be challenging in our study to target brain-intrinsic IL-34 using systemically administered neutralizing antibodies probably due to their poor brain penetrance which prevented sufficient antibody titers to efficiently neutralize biological function of IL-34 in the brain. Although two recent reports showed a reduction in microglial numbers after peripheral administration of IL-34-specific monoclonal antibodies at high doses ( 32 , 35 ), we did not observe a modulation of microglial numbers after chronic systemic antibody treatment in healthy mice or mice infected with prion disease. We found IL-34 to be ~300 times higher in the brain than CSF-1, while in the blood it was nearly absent.…”

Section: Discussioncontrasting

confidence: 99%

Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of Chronic Neurodegeneration

et al. 2020

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The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer's disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signaling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease.

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Section: Discussioncontrasting

confidence: 99%

Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of Chronic Neurodegeneration

et al. 2020

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“…The above-mentioned regional sex bias is therefore more likely indicative of a sexual dimorphism in microglia. A similar sex-biased depletion efficacy upon PLX3397 treatment in the murine cortex has recently been reported to be independent of pharmacokinetic concentrations of the drug in the brain [ 15 ]. This is in line with various studies reporting remarkable sex differences in microglia regarding key cellular functions as well as transcriptome and proteome profiles in health and disease [ 14 , 29 , 31 , 45 , 55 , 64 , 69 – 71 ].…”

Section: Discussionmentioning

confidence: 72%

“…It is furthermore conceivable that these compensatory mechanisms are differentially pronounced among sex and CNS compartment providing another possible explanation for the sex- and compartment-related differences seen in CLN1 mice upon treatment. Indeed, based on recent findings, maintenance of microglia in white matter regions appears to be highly dependent on CSF-1, whereas interleukin-34 plays a more prominent role in maintenance of gray matter microglia [ 15 ]. Depletion of both CSF-1R ligands also resulted in a more efficient depletion of microglia in the white matter, again indicating alternative survival signals in the gray matter.…”

Section: Discussionmentioning

confidence: 99%

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Berve

West²,

Martini

et al. 2020

J Neuroinflammation

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Background The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. Methods We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. Results We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1−/− mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. Conclusions Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.

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“…The fact that blocking CSF1R using small molecule inhibitors resulted in pronounced depletion of microglia in several mouse models 5,7,8,10 , further indicates that the strategy applied in this study using blocking antibodies is not favourable. Lin et al and Easley-Neal et al, provide first proof that manipulation of IL-34 can be used to modify the microglia population in the gray matter of most brain regions 32 and that this approach might be relevant in the context of inflammatory diseases and cancer 31 . We extend these findings by showing that in a model of neurodegenerative disease, which is characterized by a pronounced expansion of the microglia population predominantly in the hippocampus, inhibition of IL-34 leads to reduced microglial proliferation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

Obst

Simon

Margarida

et al. 2020

Preprint

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The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer´s disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cellular types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF1 and interleukin 34 (IL-34).Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in neurodegenerative diseases, using the ME7 model of prion disease.Selective inhibition of IL-34 showed no effects on peripheral macrophages populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34 and that this ligand plays an important role in the modulation of microglia population during neurodegeneration. Overall, our results suggest that control of microglial response through IL-34 blockade could be a potential therapeutic approach in neurodegenerative diseases.

show abstract

CSF1R Ligands IL-34 and CSF1 Are Differentially Required for Microglia Development and Maintenance in White and Gray Matter Brain Regions

Cited by 125 publications

References 58 publications

Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of Chronic Neurodegeneration

Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of Chronic Neurodegeneration

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

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