Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody

Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody

Life Science Alliance

10.26508/lsa.202402598

http://dx.doi.org/10.26508/lsa.202402598

Ee-Soo Lee, Nhi Nguyen, Barnaby E Young, Hannah Wee, Vanessa Wazny, Khang Leng Lee, Kai Yi Tay, Liuh Ling Goh, Florence WJ Chioh, Michelle CY Law, I. Russel Lee, Lay Teng Ang, Kyle M Loh, Mark Y Chan, Bingwen E Fan, Rinkoo Dalan, David C Lye, Laurent Renia, Christine Cheung

13 May 2024

Lee, E.-S., Nguyen, N., Young, B. E., Wee, H., Wazny, V., Lee, K. L., Tay, K. Y., Goh, L. L., Chioh, F. W., Law, M. C., Lee, I. R., Ang, L. T., Loh, K. M., Chan, M. Y., Fan, B. E., Dalan, R., Lye, D. C., Renia, L., & Cheung, C. (2024). Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody. Life Science Alliance, 7(7), e202402598. https://doi.org/10.26508/lsa.202402598

Subclinical vascular impairment can be exacerbated in individuals who experience sustained inflammation after COVID-19 infection. Our study explores the prevalence and impact of autoantibodies on vascular dysfunction in healthy COVID-19 survivors, an area that remains inadequately investigated. Focusing on autoantibodies against the atypical chemokine receptor 1 (ACKR1), COVID-19 survivors demonstrated significantly elevated anti-ACKR1 autoantibodies, correlating with systemic cytokines, circulating damaged endothelial cells, and endothelial dysfunction. An independent cohort linked these autoantibodies to increased vascular disease outcomes during a median 6.7-yr follow-up. We analyzed a single-cell transcriptome atlas of endothelial cells from diverse mouse tissues, identifying enrichedAckr1expressions in venous regions of the brain and soleus muscle vasculatures, which holds intriguing implications for tissue-specific venous thromboembolism manifestations reported in COVID-19. Functionally, purified immunoglobulin G (IgG) extracted from patient plasma did not trigger cell apoptosis or increase barrier permeability in human vein endothelial cells. Instead, plasma IgG enhanced antibody-dependent cellular cytotoxicity mediated by patient PBMCs, a phenomenon alleviated by blocking peptide or liposome ACKR1 recombinant protein. The blocking peptide uncovered that purified IgG from COVID-19 survivors possessed potential epitopes in the N-terminal extracellular domain of ACKR1, which effectively averted antibody-dependent cellular cytotoxicity. Our findings offer insights into therapeutic development to mitigate autoantibody reactivity in blood vessels in chronic inflammation.

Attribution 4.0 International (CC BY 4.0)

The work is funded by National Healthcare Group-National Centre for Infectious Diseases COVID-19 Centre Grant (COVID19 CG008), Ministry of Education Academic Research Fund Tier 2 (T2EP30122-0008), Vascular Research Initiative from the Lee Kong Chian School of Medicine (LKCMedicine), Nanyang Technological University, Singapore, as well as a joint Exploratory Translational Grant (ET1-2023-07) by LKCMedicine and the National Health Innovation Centre Singapore. C Cheung and KM Loh are Human Frontier Science Program Young Investigators (RGY0069/2019). LT Ang is an Additional Ventures Catalyst to Independence Fellow (980072) and is supported by the Thomas and Stacey Siebel Foundation.

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

https://oar.a-star.edu.sg/communities-collections/articles/20835

2575-1077

Infectious Disease Labs

https://www.life-science-alliance.org/content/lsa/7/7/e202402598.full.pdf