OUR SCIENCE
Publications
2024
Cell
Scott-Hewitt N, Mahoney M, Huang Y, Korte N, Yvanka de Soysa T, Wilton DK, Knorr E, Mastro K, Chang A, Zhang A, Melville D, Schenone M, Hartigan C, Stevens B
Cell. 2024 Jun; S0092-8674(24)00639-1. DOI: 10.1016/j.cell.2024.05.058
2023
Brain, Behavior, and Immunity
Aw E, Zhang Y, Yalcin E, Herrmann U, Lin SL, Langston K, Castrillon C, Ma M, Moffitt JR, Carroll MC
Brain Behav Immun. 2023 Nov; 114: 511-522. DOI: 10.1016/j.bbi.2023.06.021
Nature Medicine
Wilton DK, Mastro K, Heller MD, Gergits FW, Willing CR, Fahey JB, Frouin A, Daggett A, Gu X, Kim YA, Faull RLM, Jayadev S, Yednock T, Yang XW, Stevens B
Nat Med. 2023 Nov; 29 (11): 2866-2884. DOI: 10.1038/s41591-023-02566-3
Nature Communication
Dissing-Olesen L, Walker AJ, Feng Q, Barr HJ, Walker AC, Xie L, Wilton DK, Das I, Benowitz LI, Stevens B
Nat Commun. 2023 Sep 27; 14: 6015. DOI: 10.1038/s41467-023-41448-7
Nature
Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion
Pinho-Ribeiro FA, Deng L, Neel DV, Erdogan O, Basu H, Yang D, Choi S, Walker AJ, Carneiro-Nascimento S, He K, Wu G, Stevens B, Doran KS, Levy D, Chiu IM
Nature. 2023 Mar; 615 (7952): 472-481. DOI: 10.1038/s41586-023-05753-x
Stem Cell Reports
Small-molecule screen reveals pathways that regulate C4 secretion in stem cell-derived astrocytes
Rapino F, Natoli T, Limone F, O’Connor E, Blank J, Tegtmeyer M, Chen W, Norabuena E, Narula J, Hazelbaker D, Angelini G, Barrett L, O’Neil A, Beattie UK, Thanos JM, de Rivera H, Sheridan SD, Perlis RH, McCarroll SA, Stevens B, Subramanian A, Nehme R, Rubin LL
Stem Cell Reports. 2023 Jan; 18 (1): 237-253. DOI: 10.1016/j.stemcr.2022.11.018
2021
Advances in Immunology
Neuropsychiatric disorders: An immunological perspective
Aw E, Zhang Y, Yalcin E, Herrmann US, Carroll MC
Adv Immunol. 2021 Nov; 152: 83-155. DOI: 10.1016/bs.ai.2021.09.002
Nature Neuroscience
Yilmaz M, Yalcin E, Presumey J, Aw E, Ma M, Whelan CW, Stevens B, McCarroll SA, Carroll MC
This paper presents a comprehensive analysis of the impact of human C4A and C4B expression and dosage effects in humanized mouse models. hC4A and hC4B display differences in synaptic tagging and downstream phenotypes, consistent with the differential schizophrenia risk profile of these isotypes. Overexpression of hC4A results in increased synaptic pruning by microglia, altered circuit development, and changes in behavior. These results strongly support a role for neuroimmune mechanisms in prefrontal circuit development and psychiatric vulnerability, and advance the pruning hypothesis of schizophrenia.
Nat Neurosci. 2021 Feb; 24 (2): 214-224. DOI: 10.1038/s41593-020-00763-8
2020
Journal of Immunology
Pedersen H, Jensen RK, Jensen JMB, Fox R, Pedersen DV, Olesen HG, Hansen AG, Christiansen D, Mazarakis SMM, Lojek N, Hansen P, Gadeberg TAF, Zarantonello A, Laursen NS, Mollnes TE, Johnson MB, Stevens B, Thiel S, Andersen GR
J Immunol. 2020 Oct 15; 205 (8): 2287-2300. DOI: 10.4049/jimmunol.2000752
Trends in Immunology
Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime?
Liddelow SA, Marsh SE, Stevens B
Trends Immunol. 2020 Sep; 41 (9): 820-835. DOI: 10.1016/j.it.2020.07.006
Journal of Immunology
Zarantonello A, Presumey J, Simoni L, Yalcin E, Fox R, Hansen A, Olesen HG, Thiel S, Johnson MB, Stevens B, Laursen NS, Carroll MC, Andersen GR
J Immunol. 2020 Sep 15; 205 (6): 1678-1694. DOI: 10.4049/jimmunol.2000528
The EMBO Journal
Local Externalization of Phosphatidylserine Mediates Developmental Synaptic Pruning by Microglia
Scott-Hewitt N, Perrucci F, Morini R, Erreni M, Mahoney M, Witkowska A, Carey A, Faggiani E, Schuetz LT, Mason S, Tamborini M, Bizzotto M, Passoni L, Filipello F, Jahn R, Stevens B, Matteoli M
This paper describes regulation and consequences of phosphatidylserine exposure on neuronal and synaptic membranes, which may serve to recruit or regulate complement activity at synapses and their downstream phagocytosis by microglia.
EMBO J. 2020 Aug 17;39(16):e105380. DOI: 10.15252/embj.2020105380
Nature
Complement Genes Contribute Sex-Biased Vulnerability in Diverse Disorders
Kamitaki N, Sekar A, Handsaker RE, de Rivera H, Tooley K, Morris DL, Taylor KE, Whelan CW, Tombleson P, Loohuis LMO; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Boehnke M, Kimberly RP, Kaufman KM, Harley JB, Langefeld CD, Seidman CE, Pato MT, Pato CN, Ophoff RA, Graham RR, Criswell LA, Vyse TJ, McCarroll SA
This paper elucidates the differential risk profiles arising from C4 locus genetic variation for men and women, and the complex relationships between C4A-related risk for schizophrenia versus autoimmune disorders such as lupus. The McCarroll lab also presents here foundational data on complement component C3 and C4 protein levels in the CSF across the lifespan of healthy adults, demonstrating that sex and age effects, in addition to C4 genotype, are highly significant covariates in any consideration of complement as fluid biomarkers. Finally, this paper also describes a computational method and data resource for imputing C4 genotypes from SNP data, which will be highly useful in a variety of research and translational contexts considering the complex influence of C4 variation on complement expression and disease risk.
Nature. 2020 Jun;582(7813):577-581. DOI: 10.1038/s41586-020-2277-x
2019
Immunity
Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits F, Segel M, Nemesh J, Marsh SE, Saunders A, Macosko E, Ginhoux F, Chen J, Franklin RJM, Piao X, McCarroll SA, Stevens B
We analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers.
Immunity. 2019 Jan 15;50(1):253-271.e6. DOI: 10.1016/j.immuni.2018.11.004
2018
Neuron
CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development
Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST, Frouin A, Walker AJ, Heller MD, Umemori H, Chen C, Stevens B
Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs.
Neuron. 2018 Oct 10;100(1):120-134.e6. DOI: 10.1016/j.neuron.2018.09.017
Annual Review of Cell and Developmental Biology
Microglia and the Brain: Complementary Partners in Development and Disease
Hammond TR, Robinton D, Stevens B.
In this review, we discuss the crucial roles that microglia play in shaping the brain – from their influence on neurons and glia within the developing CNS to their roles in synaptic maturation and brain wiring – as well as some of the obstacles to overcome when assessing their contributions to normal brain development. Furthermore, we examine how normal developmental functions of microglia are perturbed or remerge in neurodevelopmental and neurodegenerative disease.
Annu Rev Cell Dev Biol. 2018 Oct 6:34:523-544. DOI: 10.1146/annurev-cellbio-100616-060509
2016
Nature
Schizophrenia risk from complex variation of complement component 4
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ, Carroll MC, Stevens B, McCarroll SA.
The results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
Nature. 2016 Feb 11;530(7589):177-83. DOI: 10.1038/nature16549