Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation

Momin, N.; Pabel, S.; Rudra, A.; Kumowski, N.; Lee, I.-H.; Mentkowski, K.; Yamazoe, M.; Stengel, L.; Muse, C. G.; Seung, H.; Paccalet, A.; Gonzalez-Correa, C.; Jacobs, E. B.; Grune, J.; Schloss, M. J.; Sossalla, S.; Wojtkiewicz, G.; Iwamoto, Y.; McMullen, P.; Mitchell, R. N.; Ellinor, P. T.; Anderson, D. G.; Naxerova, K.; Nahrendorf, M.; Hulsmans, M.

doi:10.1101/2024.08.10.607461

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bioRxiv · 10.1101/2024.08.10.607461

Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation

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Abstract

Atrial fibrillation (AFib) and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2+ macrophages secrete osteopontin (encoded by Spp1), a matricellular signaling protein that engenders fibrosis and AFib. Here we show that silencing Spp1 in TREM2+ cardiac macrophages with an antibody-siRNA conjugate reduces atrial fibrosis and suppresses AFib in mice, thus offering a new immunotherapy for the most common arrhythmia.

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Momin, N., Pabel, S., Rudra, A., Kumowski, N., Lee, I.-H., Mentkowski, K., Yamazoe, M., Stengel, L., Muse, C. G., Seung, H., Paccalet, A., Gonzalez-Correa, C., Jacobs, E. B., Grune, J., Schloss, M. J., Sossalla, S., Wojtkiewicz, G., Iwamoto, Y., McMullen, P., Mitchell, R. N., Ellinor, P. T., Anderson, D. G., Naxerova, K., Nahrendorf, M., Hulsmans, M.. 2024-08-10. Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation. https://doi.org/10.1101/2024.08.10.607461

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