CHIP disrupts monocyte-endothelial interactions across multiple tissues to promote vascular inflammation in humans

Background Clonal hematopoiesis of indeterminate potential (CHIP) occurs when hematopoietic stem cells acquire mutations that confer a proliferative advantage. CHIP is associated with increased risk of multiple vascular diseases. Mouse models have identified CHIP monocytes as highly proinflammatory. Here we seek to build on these earlier studies by characterizing adipose tissue macrophages and vascular cells in patients with CHIP. Methods We performed single-cell RNA sequencing on paired peripheral blood mononuclear cells and subcutaneous adipose tissue from 6 CHIP patients and 6 matched controls. We analyzed cell type specific gene expression profiles and intercellular interactions. Results We found that macrophages had an exaggerated proinflammatory profile compared to circulating monocytes. We also found increased interaction between circulating CD14+ monocytes and endothelial cells. Specifically, cells from patients with CHIP showed enhanced signaling related to leukocyte transendothelial migration. These differences were tissue specific. We recapitulated monocyte-endothelial cell interactions in single cell RNA sequencing data from a mouse model of CHIP. Conclusions Monocytes from patients with CHIP have increased endothelial interaction compared to controls and macrophages from patients with CHIP are highly proinflammatory. Alterations in the monocyte-endothelial interaction in CHIP likely contribute to cardiovascular disease risk. ![Figure][1] Graphical abstract ### Competing Interest Statement AGB is a scientific co-founder of TenSixteen Bio. ### Funding Statement This study was funded by the following: K23DK135414 (SSB, JRK), Doris Duke CSDA 2021193 (CNW), K23 HL156759 (CNW), Burroughs Wellcome Fund 1021480 (CNW), R01 DK112262 (JRK), the Tennessee Center for AIDS Research grant P30 AI110527 (Supplement CNW, JK), the Vanderbilt Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA068485). This work was also supported by NIH Early Independence Award grant DP5 OD029586, a Burroughs Wellcome Fund Career Award for Medical Scientists, a Pew-Stewart Scholar for Cancer Research award, supported by the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust (AGB). ### 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: The Institutional Review Board (IRB # 161254) of Vanderbilt University gave ethical approval for this work. 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 [1]: pending:yes