Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Abstract

Genetically caused neurological disorders of the central nervous system (CNS) usually result in poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with disease‐amplifying neuroinflammation, a feature shared by progressive forms of multiple sclerosis (PMS), another poorly treatable disorder of the CNS. We have previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients fulfilling clinical criteria for multiple sclerosis (MS). These mutations cause a loss of function of the gene product resulting in a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation comprising adaptive immune reactions promotes disease progression in these PLP1 mutant models, opening the possibility to improve disease outcome of the respective disorders by targeting/modulating inflammation. We here show that PLX3397, a potent inhibitor of the CSF‐1R and targeting innate immune cells, attenuates neuroinflammation in our models by reducing numbers of resident microglia and attenuating T‐lymphocyte recruitment in the CNS. This leads to an amelioration of demyelination, axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the inner retinal composite layer in longitudinal studies using noninvasive optical coherence tomography. Our findings identify microglia as important promoters of neuroinflammation‐related neural damage and CSF‐1R inhibition as a possible therapeutic strategy not only for PMS but also for inflammation‐related genetic diseases of the nervous system for which causal treatment options are presently lacking.

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

“…We recently applied a CSF-1R inhibitor targeting CSF-1R-dependent microglia in another hereditary CNS disease model. Mice carrying point mutations in the PLP1 gene that have previously been found in multiple sclerosis patients [ 20 , 23 , 72 ] were successfully treated with PLX3397 which attenuated neuroinflammation-related neural damage [ 24 ], adding to the growing evidence that microglial reactions play important roles in a plethora of CNS disorders comprising genetically mediated diseases [ 26 , 65 ].…”

Cien Años de Microglía: Milestones in a Century of Microglial Research

“…However, their absolute specificity for microglia has been recently questioned [115]. On the pharmacological front, drugs targeting M-CSF receptor have been recently developed by the company Plexxikon to eliminate and repopulate microglia, with conflicting results about the beneficial or detrimental effects of ablating them [80,109,[116][117][118][119][120][121][122]. However, dead microglia are unlikely to vanish from the parenchyma without collateral effects and the field will benefit from the development of novel drugs and nanomaterials that allow targeting specific microglial populations or specific microglial functions.…”

Microglia roles in synaptic plasticity and myelination in homeostatic conditions and neurodevelopmental disorders

“…This excess inflammation may eventually lead to neurotoxicity and neuronal death. Microglia‐related treatments that result in microglial regulation have been shown to be effective in ameliorating deficits and promoting remyelination in pathological conditions (Butovsky et al, ; Groh et al, ; Janova et al, )…”

“…However, in disorders involving myelination deficits, microglia may be compromised in their ability to phagocytose myelin debris and support OLs (Butovsky et al, 2006b;Zhou et al, 2015). In other pathological conditions, microglia can be overactivated and secrete high levels of inflammatory factors and radicals (Ekdahl, Kokaia, & Lindvall, 2009;Groh, Klein, Berve, West, & Martini, 2018;Kim, Hong, & Bae, 2018). This excess inflammation may eventually lead to neurotoxicity and neuronal death.…”

“…This excess inflammation may eventually lead to neurotoxicity and neuronal death. Microglia-related treatments that result in microglial regulation have been shown to be effective in ameliorating deficits and promoting remyelination in pathological conditions (Butovsky et al, 2006a;Groh et al, 2018;Janova et al, 2018) their inflammatory effect, improved sociability in humans (Taliou et al, 2013;Theoharides, Asadi, & Panagiotidou, 2012), and attenuated autistic-like behaviors in mice (Bertolino et al, 2017). Interestingly, gastrointestinal disturbances have also been suggested to influence the severity of symptoms in children with ASD (Adams, Johansen, Powell, Quig, & Rubin, 2011).…”