Extra-axial inflammatory signal and its relation to peripheral and central immunity in depression

Although both central and peripheral inflammation have been consistently observed in depression, the relationship between the two remains obscure. Extra-axial immune cells may play a role in mediating the connection between central and peripheral immunity. This study investigates the potential roles of calvarial bone marrow and parameningeal spaces in mediating interactions between central and peripheral immunity in depression. Positron emission tomography was employed to measure regional TSPO expression in the skull and parameninges as a marker of inflammatory activity. This measure was correlated with brain TSPO expression and peripheral cytokine concentrations in a cohort enriched for heightened peripheral and central immunity comprising 51 individuals with depression and 25 healthy controls. The findings reveal a complex relationship between regional skull TSPO expression and both peripheral and central immunity. Facial and parietal skull bone TSPO expression showed significant associations with both peripheral and central immunity. TSPO expression in the confluence of sinuses was also linked to both central and peripheral immune markers. Group dependant elevations in TSPO expression within the occipital skull bone marrow were also found to be significantly associated with central inflammation. Significant associations between immune activity within the skull, parameninges, parenchyma, and periphery highlight the role of the skull bone marrow and venous sinuses as pivotal sites for peripheral and central immune interactions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The BIODEP study was jointly sponsored by the Cambridgeshire and Peterborough NHS Foundation Trust and the University of Cambridge. Financial support for the project included a strategic award from the Wellcome Trust (Grant No. 104025 [to ETB, CMP, FET]) in partnership with Janssen, GlaxoSmithKline, Lundbeck, and Pfizer; a Senior Investigator award from the National Institute of Health Research (NIHR) (to ETB and CMP); MRC is supported by an NIHR Research Professorship RP-2017-08-ST2-002). Contributions from the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and Kings College London; and the NIHR Cambridge Biomedical Research Centre (Mental Health and Immunity/Infection/Transplantation Themes, NIHR203312). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Recruitment of participants was facilitated by the NIHR Clinical Research Network: Kent, Surrey and Sussex, and Eastern. Collection and management of data was carried out using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at the University of Cambridge. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical endorsement for this study was secured from the National Research Ethics Service Committee East of England, Cambridge Central (REC reference: 15/EE/0092), and the research design adhered to the directives set forth by the UK Administration of Radioactive Substances Advisory Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding authors upon reasonable request.