Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation

Noor Momin; Steffen Pabel; Arnab Rudra; Nina Kumowski; I-Hsiu Lee; Kyle Mentkowski; Masahiro Yamazoe; Laura Stengel; Charlotte G Muse; Hana Seung; Alexandre Paccalet; Cristina Gonzalez-Correa; Emily B Jacobs; Jana Grune; Maximilian J Schloss; Samuel Sossalla; Gregory Wojtkiewicz; Yoshiko Iwamoto; Patrick McMullen; Richard N Mitchell; Patrick T Ellinor; Daniel G Anderson; Kamila Naxerova; Matthias Nahrendorf; Maarten Hulsmans

doi:10.1101/2024.08.10.607461

Therapeutic Spp1 silencing in TREM2⁺ cardiac macrophages suppresses atrial fibrillation

bioRxiv [Preprint]. 2024 Aug 10:2024.08.10.607461. doi: 10.1101/2024.08.10.607461.

Authors

Noor Momin^{1

2

3

4}, Steffen Pabel^{1

2

5

6}, Arnab Rudra^{7

8

9

10

11}, Nina Kumowski^{1

2

5}, I-Hsiu Lee^{1

2

5

12}, Kyle Mentkowski^{1

2

5}, Masahiro Yamazoe^{1

2}, Laura Stengel⁶, Charlotte G Muse^{1

2

5}, Hana Seung^{1

2

5}, Alexandre Paccalet^{1

2

5}, Cristina Gonzalez-Correa^{1

2}, Emily B Jacobs^{3

4}, Jana Grune^{1

2}, Maximilian J Schloss^{1

2}, Samuel Sossalla¹³, Gregory Wojtkiewicz^{1

2}, Yoshiko Iwamoto^{1

2}, Patrick McMullen^{7

8

9

10

11}, Richard N Mitchell¹⁴, Patrick T Ellinor^{15

16}, Daniel G Anderson^{7

8

9

10

11}, Kamila Naxerova¹², Matthias Nahrendorf^{1

2

5

15

17}, Maarten Hulsmans^{1

2}

Affiliations

¹ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Center for Precision Engineering for Health, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.
⁷ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA.
⁸ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹² Blavatnik Institute, Genetics, Harvard Medical School, Boston, MA, USA.
¹³ Department of Cardiology, University Hospital Giessen, Kerckhoff Clinic Bad Nauheim, and DZHK, Partner site RhineMain, Germany.
¹⁴ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁵ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶ Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
¹⁷ Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany.

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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Abstract

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