Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury

Norris, Geoffrey T.; Smirnov, Igor; Filiano, Anthony J.; Shadowen, Hannah; Cody, Kris R.; Thompson, Jeremy; Harris, Tajie H.; Gaultier, Alban; Overall, Christopher C.; Kipnis, Jonathan

doi:10.1084/jem.20172244

Cited by 93 publications

(83 citation statements)

References 70 publications

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“…The increased iC3b deposition in the ONL upon the onset of photoreceptor degeneration, elevated retinal expression of Cd11b , a component of the CR3, and the ONL translocation of CR3-expressing microglia, point to increased microglia–photoreceptor interactions via iC3b-CR3 binding ( Bajic et al, 2013 ; Xu et al, 2017 ) as part of an adaptive complement response. C3–CR3 interaction has been previously demonstrated as a molecular mechanism employed by microglia to eliminate supernumerary synapses during normal brain development ( Stevens et al, 2007 ) and to clear synaptic debris following injury-induced synaptic degeneration ( Norris et al, 2018 ), but which may drive maladaptive phagocytosis of synapses in certain CNS pathologies ( Berg et al, 2012 ; Hong et al, 2016 ). Additionally, iC3b-CR3 function in microglia has also been shown to mediate beneficial clearance of apoptotic neurons ( Elward and Gasque, 2003 ) and extracellular debris ( Fu et al, 2012 ; Hadas et al, 2012 ) following neural injury via phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

Silverman

Wang

et al. 2019

Journal of Experimental Medicine

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Complement activation has been implicated as contributing to neurodegeneration in retinal and brain pathologies, but its role in retinitis pigmentosa (RP), an inherited and largely incurable photoreceptor degenerative disease, is unclear. We found that multiple complement components were markedly up-regulated in retinas with human RP and the rd10 mouse model, coinciding spatiotemporally with photoreceptor degeneration, with increased C3 expression and activation localizing to activated retinal microglia. Genetic ablation of C3 accelerated structural and functional photoreceptor degeneration and altered retinal inflammatory gene expression. These phenotypes were recapitulated by genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product iC3b, implicating C3-CR3 signaling as a regulator of microglia–photoreceptor interactions. Deficiency of C3 or CR3 decreased microglial phagocytosis of apoptotic photoreceptors and increased microglial neurotoxicity to photoreceptors, demonstrating a novel adaptive role for complement-mediated microglial clearance of apoptotic photoreceptors in RP. These homeostatic neuroinflammatory mechanisms are relevant to the design and interpretation of immunomodulatory therapeutic approaches to retinal degenerative disease.

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Section: Discussionmentioning

confidence: 99%

C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

Silverman

Wang

et al. 2019

Journal of Experimental Medicine

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“…Complement has also been implicated in microglial elimination of synapses in AD, mediating pathological loss of synapses in AD mouse models (Hong et al, 2016;Shi et al, 2017). Complement is also involved in synaptic loss in response to acute brain injury (Alawieh, Langley, Weber, Adkins, & Tomlinson, 2018;Norris et al, 2018), chronic tau accumulation (Dejanovic et al, 2018), epilepsy (Wyatt, Witt, Barbaro, Cohen-Gadol, & Brewster, 2017), neuroinflammation (Watkins et al, 2016), and other disease contexts (Sekar et al, 2016). Other microglial signaling components also have important functions in both brain development and neurodegeneration, including CX3CR1 (Basilico et al, 2019;Paolicelli et al, 2011;Sheridan & Murphy, 2013) and progranulin (Baker et al, 2006;Lui et al, 2016), further illustrating that common mechanisms can mediate important microglial functions in brain health and disease (Tenner, Stevens, & Woodruff, 2018).…”

Section: Introductionmentioning

confidence: 99%

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Jay

Saucken

Muñoz

et al. 2019

Glia

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Variants in the microglial receptor TREM2 confer risk for multiple neurodegenerative diseases. However, it remains unknown how this receptor functions on microglia to modulate these diverse neuropathologies. To understand the role of TREM2 on microglia more generally, we investigated changes in microglial function in Trem2−/− mice. We found that loss of TREM2 impairs normal neurodevelopment, resulting in reduced synapse number across the cortex and hippocampus in 1‐month‐old mice. This reduction in synapse number was not due directly to alterations in interactions between microglia and synapses. Rather, TREM2 was required for microglia to limit synaptic engulfment by astrocytes during development. While these changes were largely normalized later in adulthood, high fat diet administration was sufficient to reinitiate TREM2‐dependent modulation of synapse loss. Together, this identifies a novel role for microglia in instructing synaptic pruning by astrocytes to broadly regulate appropriate synaptic refinement, and suggests novel candidate mechanisms for how TREM2 and microglia could influence synaptic loss in brain injury and disease.

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“…Moreover, the other genes including Kdr , S1pr1 , Ubc , Grm2 , Pdyn , and Itgam are possible candidates for ASD due to the related molecular functions. For examples, S1pr1 regulates multiple aspects of sensory neuron and immune system functions [Healy & Antel, ]; Ubc encodes a ubiquitin C and participates in neuronal development and maintenance; Grm2 is associated with depression and memory network related to glutamatergic synapse [Jin et al, ; Lyon et al, ]; Pdyn encodes a prodynorphin, which is closely related to drug abuse and synaptic plasticity [Henriksson et al, ]; and Itgam has been reported to be involved in the debris clearance of microglia [Norris et al, ]. Therefore, it is possible that the misregulation of these genes contributes to certain phenotypes of ASD.…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

et al. 2019

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Genetic mutations are the major pathogenic factor of Autism Spectrum Disorder (ASD). In recent years, more and more ASD risk genes have been revealed, among which there are a group of transcriptional regulators. Considering the similarity of the core clinical phenotypes, it is possible that these different factors may regulate the expression levels of certain key targets. Identification of these targets could facilitate the understanding of the etiology and developing of novel diagnostic and therapeutic methods. Therefore, we performed integrated transcriptome analyses of RNA‐Seq and microarray data in multiple ASD mouse models and identified a number of common downstream genes in various brain regions, many of which are related to the structure and function of the synapse components or drug addiction. We then established protein–protein interaction networks of the overlapped targets and isolated the hub genes by 11 algorithms based on the topological structure of the networks, including Sdc4, Vegfa, and Cp in the Cortex‐Adult subgroup, Gria1 in the Cortex‐Juvenile subgroup, and Kdr, S1pr1, Ubc, Grm2, Grin2b, Nrxn1, Pdyn, Grin3a, Itgam, Grin2a, Gabra2, and Camk4 in the Hippocampus‐Adult subgroup, many of which have been associated with ASD in previous studies. Finally, we cross compared our results with human brain transcriptional data sets and verified several key candidates, which may play important role in the pathology process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRIN2A, GABRA2, and CAMK4. In summary, by integrated bioinformatics analysis, we have identified a series of potentially important molecules for future ASD research. Autism Res 2020, 13: 352–368. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Abnormal transcriptional regulation accounts for a significant portion of Autism Spectrum Disorder. In this study, we performed transcriptome analyses of mouse models to identify common downstream targets of transcriptional regulators involved in ASD. We identified several recurrent target genes that are close related to the common pathological process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRM2, NRXN1, GRIN3A, ITGAM, GRIN2A, GABRA2, and CAMK4. These results provide potentially important targets for understanding the molecular mechanism of ASD.

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Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury

Abstract: Norris et al. show that microglia are the key phagocytes in removal of synaptic debris in the dorsal lateral geniculate nucleus after optic nerve injury. This microglial function is dependent on recognition of neurodegeneration and is mediated by the complement system.

Cited by 93 publications

References 70 publications

C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

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