{"doi":"10.1186/s40478-021-01226-2","title":"Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study","abstract":"<jats:title>Abstract</jats:title><jats:p>Activation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of <jats:italic>C2</jats:italic>, <jats:italic>C3</jats:italic> and <jats:italic>C4</jats:italic> expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.</jats:p>","journal":"Acta Neuropathologica Communications","year":2021,"id":644747,"datarank":1.2264222352601433,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"self_citation_contribution":0.5983476069846413,"citation_network_contribution":0.6280746282755019,"self_endowment_contribution":0.5983476069846413,"citer_contribution":0.6280746282755019,"corpus_percentile":null,"corpus_rank":null,"citation_count":53,"citer_count":41,"citers_with_citation_signal":31,"citers_with_endowment":31,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":943319,"name":"Mamatha Mandava","orcid":"0000-0003-3734-1215","position":1,"is_corresponding":false},{"id":793016,"name":"Silvia Guglietta","orcid":"0000-0001-9998-5716","position":2,"is_corresponding":false},{"id":280460,"name":"Stephen Tomlinson","orcid":"0000-0002-6281-2122","position":3,"is_corresponding":false},{"id":283197,"name":"Amer Toutonji","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study","abstract":"<jats:title>Abstract</jats:title><jats:p>Activation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of <jats:italic>C2</jats:italic>, <jats:italic>C3</jats:italic> and <jats:italic>C4</jats:italic> expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.</jats:p>","is_dataset_classified":null,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34281628","pmcid":"PMC8287781","openalex_id":"https://openalex.org/W3183938588","authors":[],"funders":[{"funder_name":"U.S. Department of Veterans Affairs","grant_id":"1BX004256","title":null},{"funder_name":"U.S. Department of Veterans Affairs","grant_id":"1RX001141","title":null},{"funder_name":"U.S. Department of Veterans Affairs","grant_id":"IK6BX005235","title":null},{"funder_name":"BLRD VA","grant_id":"I01 BX004256","title":null},{"funder_name":"RRD VA","grant_id":"I01 RX001141","title":null},{"funder_name":"National Institutes of Health","grant_id":"1IK6BX005235-01","title":"BLR&D Research Career Scientist Award Application for Dr. Stephen Tomlinson"}],"total_grants":6,"fwci":3.0722,"citation_percentile":0.92425934,"influential_citations":0,"citation_trend":[{"year":2021,"count":1},{"year":2022,"count":3},{"year":2023,"count":14},{"year":2024,"count":18},{"year":2025,"count":10},{"year":2026,"count":7}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://actaneurocomms.biomedcentral.com/track/pdf/10.1186/s40478-021-01226-2","host_type":"journal"},{"url":"https://actaneurocomms.biomedcentral.com/track/pdf/10.1186/s40478-021-01226-2","host_type":"publisher"},{"url":"https://link.springer.com/content/pdf/10.1186/s40478-021-01226-2.pdf","host_type":"publisher"},{"url":"https://link.springer.com/article/10.1186/s40478-021-01226-2/fulltext.html","host_type":"publisher"},{"url":"https://doi.org/10.1186/s40478-021-01226-2","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/34281628","host_type":"repository"},{"url":"https://doaj.org/article/8d118b7d7f7446a48691112bf2210d8e","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8287781","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8287781","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8287781?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1186/s40478-021-01226-2","host_type":""},{"url":"https://dx.doi.org/10.1186/s40478-021-01226-2","host_type":""}],"fields_of_study":["Neuroinflammation and Neurodegeneration Mechanisms","Traumatic Brain Injury and Neurovascular Disturbances","Neonatal and fetal brain pathology","0301 basic medicine","03 medical and health sciences","0303 health sciences"],"mesh_terms":["Brain Injuries, Traumatic","Neuroinflammatory Diseases","Animals","Brain","Complement Activation","Complement C2","Complement C3","Complement C4","Recombinant Fusion Proteins","Brain Injury, Chronic","Gene Expression Profiling","Complement Inactivating Agents","Mice","Transcriptome"],"keywords":["Neuroinflammation","Complement system","Neuroprotection","Traumatic brain injury","Downregulation and upregulation","Astrogliosis","Inflammation","Medicine","Transcriptome","Neuroscience","Gene expression","Immunology","Immune system","Biology","Central nervous system","Gene","Complement Inhibition","Nanostring","Recombinant Fusion Proteins","Mice","Brain Injuries, Traumatic","Brain Injury, Chronic","Animals","RC346-429","Complement Activation","Research","Gene Expression Profiling","Brain","Complement C4","Complement C3","Complement C2","Complement Inactivating Agents","Neuroinflammatory Diseases","Neurology. Diseases of the nervous system"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T02:00:02.395133Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}