Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation
Macrophage-mediated IL-6 signaling drives ryanodine receptor–2 calcium leak in postoperative atrial fibrillation Joshua A. Keefe, Yuriana Aguilar-Sanchez, J. Alberto Navarro-Garcia, Isabelle Ong, Luge Li, Amelie Paasche, Issam Abu-Taha, Marcel A. Tekook, Florian Bruns, Shuai Zhao, Markus Kamler, Yin...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 6, 2025
|
| In: |
The journal of clinical investigation
Year: 2025, Volume: 135, Issue: 9, Pages: 1-17 |
| ISSN: | 1558-8238 |
| DOI: | 10.1172/JCI187711 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1172/JCI187711 Verlag, kostenfrei, Volltext: https://www.jci.org/articles/view/187711 
|
| Author Notes: | Joshua A. Keefe, Yuriana Aguilar-Sanchez, J. Alberto Navarro-Garcia, Isabelle Ong, Luge Li, Amelie Paasche, Issam Abu-Taha, Marcel A. Tekook, Florian Bruns, Shuai Zhao, Markus Kamler, Ying H. Shen, Mihail G. Chelu, Na Li, Dobromir Dobrev, and Xander H.T. Wehrens |
MARC
| LEADER | 00000naa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1945738863 | ||
| 003 | DE-627 | ||
| 005 | 20251210123358.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 251210s2025 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1172/JCI187711 |2 doi | |
| 035 | |a (DE-627)1945738863 | ||
| 035 | |a (DE-599)KXP1945738863 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Keefe, Joshua Anthony |e VerfasserIn |0 (DE-588)138394041X |0 (DE-627)1945739681 |4 aut | |
| 245 | 1 | 0 | |a Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation |c Joshua A. Keefe, Yuriana Aguilar-Sanchez, J. Alberto Navarro-Garcia, Isabelle Ong, Luge Li, Amelie Paasche, Issam Abu-Taha, Marcel A. Tekook, Florian Bruns, Shuai Zhao, Markus Kamler, Ying H. Shen, Mihail G. Chelu, Na Li, Dobromir Dobrev, and Xander H.T. Wehrens |
| 264 | 1 | |c March 6, 2025 | |
| 300 | |b Illustrationen | ||
| 300 | |a 17 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 10.12.2025 | ||
| 520 | |a Macrophage-mediated IL-6 signaling drives ryanodine receptor–2 calcium leak in postoperative atrial fibrillation Joshua A. Keefe, Yuriana Aguilar-Sanchez, J. Alberto Navarro-Garcia, Isabelle Ong, Luge Li, Amelie Paasche, Issam Abu-Taha, Marcel A. Tekook, Florian Bruns, Shuai Zhao, Markus Kamler, Ying H. Shen, Mihail G. Chelu, Na Li, Dobromir Dobrev, Xander H.T. WehrensJ Clin Invest. 2025;135(9):e187711. https://doi.org/10.1172/JCI187711. Postoperative atrial fibrillation (poAF) is AF occurring days after surgery, with a prevalence of 33% among patients undergoing open-heart surgery. The degree of postoperative inflammation correlates with poAF risk, but less is known about the cellular and molecular mechanisms driving postoperative atrial arrhythmogenesis. We performed single-cell RNA-seq comparing atrial nonmyocytes from mice with and without poAF, which revealed infiltrating CCR2+macrophages to be the most altered cell type. Pseudotime trajectory analyses identified Il-6 as a gene of interest driving in macrophages, which we confirmed in pericardial fluid collected from human patients after cardiac surgery. Indeed, macrophage depletion and macrophage-specific Il6ra conditional knockout (cKO) prevented poAF in mice. Downstream STAT3 inhibition with TTI-101 and cardiomyocyte-specific Stat3 cKO rescued poAF, indicating a proarrhythmogenic roleof STAT3 in poAF development. Confocal imaging in isolated atrial cardiomyocytes (ACMs) uncovered what we believe to be a novel link between STAT3 and CaMKII-mediated ryanodine receptor–2 (RyR2)-Ser(S)2814 phosphorylation. Indeed, nonphosphorylatable RyR2S2814A mice were protected from poAF, and CaMKII inhibition prevented arrhythmogenic Ca2+ mishandling in ACMs from mice with poAF. Altogether, we provide multiomic, biochemical, and functional evidence frommice and humans that IL-6-STAT3-CaMKII signaling driven by infiltrating atrial macrophages is a pivotal driver of poAF, which portends therapeutic utility for poAF prevention. | ||
| 700 | 1 | |a Aguilar-Sanchez, Yuriana |e VerfasserIn |4 aut | |
| 700 | 1 | |a Navarro-Garcia, J. Alberto |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ong, Isabelle |e VerfasserIn |4 aut | |
| 700 | 1 | |a Li, Luge |e VerfasserIn |4 aut | |
| 700 | 1 | |a Paasche, Amelie |e VerfasserIn |0 (DE-588)1258391082 |0 (DE-627)1804367095 |4 aut | |
| 700 | 1 | |a Abu-Taha, Issam |e VerfasserIn |4 aut | |
| 700 | 1 | |a Tekook, Marcel A. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Bruns, Florian |e VerfasserIn |4 aut | |
| 700 | 1 | |a Zhao, Shuai |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kamler, Markus |e VerfasserIn |4 aut | |
| 700 | 1 | |a Shen, Ying H. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Chelu, Mihail G. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Li, Na |e VerfasserIn |4 aut | |
| 700 | 1 | |a Dobrev, Dobromir |e VerfasserIn |4 aut | |
| 700 | 1 | |a Wehrens, Xander H. T. |e VerfasserIn |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The journal of clinical investigation |d Ann Arbor, Mich. : ASCJ, 1924 |g 135(2025), 9, Artikel-ID e187711, Seite 1-17 |h Online-Ressource |w (DE-627)316004677 |w (DE-600)2018375-6 |w (DE-576)094950423 |x 1558-8238 |7 nnas |a Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation |
| 773 | 1 | 8 | |g volume:135 |g year:2025 |g number:9 |g elocationid:e187711 |g pages:1-17 |g extent:17 |a Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation |
| 856 | 4 | 0 | |u https://doi.org/10.1172/JCI187711 |x Verlag |x Resolving-System |z kostenfrei |3 Volltext |7 0 |
| 856 | 4 | 0 | |u https://www.jci.org/articles/view/187711 |x Verlag |z kostenfrei |3 Volltext |7 0 |
| 951 | |a AR | ||
| 992 | |a 20251210 | ||
| 993 | |a Article | ||
| 994 | |a 2025 | ||
| 998 | |g 1258391082 |a Paasche, Amelie |m 1258391082:Paasche, Amelie |d 50000 |e 50000PP1258391082 |k 0/50000/ |p 6 | ||
| 999 | |a KXP-PPN1945738863 |e 4826094566 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"relHost":[{"id":{"eki":["316004677"],"zdb":["2018375-6"],"issn":["1558-8238"]},"origin":[{"publisher":"ASCJ","dateIssuedKey":"1924","dateIssuedDisp":"1924-","publisherPlace":"Ann Arbor, Mich."}],"physDesc":[{"extent":"Online-Ressource"}],"title":[{"title":"The journal of clinical investigation","subtitle":"JCI ; the publication of the American Society for Clinical Investigation","title_sort":"journal of clinical investigation"}],"titleAlt":[{"title":"JCI"}],"part":{"year":"2025","issue":"9","pages":"1-17","volume":"135","text":"135(2025), 9, Artikel-ID e187711, Seite 1-17","extent":"17"},"pubHistory":["1.1924/25 -"],"recId":"316004677","corporate":[{"display":"American Society for Clinical Investigation","roleDisplay":"Herausgebendes Organ","role":"isb"}],"language":["eng"],"disp":"Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillationThe journal of clinical investigation","type":{"bibl":"periodical","media":"Online-Ressource"},"note":["Gesehen am 25.01.2022","Fortsetzung der Druck-Ausgabe"]}],"physDesc":[{"extent":"17 S.","noteIll":"Illustrationen"}],"id":{"doi":["10.1172/JCI187711"],"eki":["1945738863"]},"origin":[{"dateIssuedKey":"2025","dateIssuedDisp":"March 6, 2025"}],"name":{"displayForm":["Joshua A. Keefe, Yuriana Aguilar-Sanchez, J. Alberto Navarro-Garcia, Isabelle Ong, Luge Li, Amelie Paasche, Issam Abu-Taha, Marcel A. Tekook, Florian Bruns, Shuai Zhao, Markus Kamler, Ying H. Shen, Mihail G. Chelu, Na Li, Dobromir Dobrev, and Xander H.T. Wehrens"]},"language":["eng"],"recId":"1945738863","note":["Gesehen am 10.12.2025"],"type":{"media":"Online-Ressource","bibl":"article-journal"},"title":[{"title":"Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation","title_sort":"Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation"}],"person":[{"roleDisplay":"VerfasserIn","display":"Keefe, Joshua Anthony","role":"aut","family":"Keefe","given":"Joshua Anthony"},{"role":"aut","display":"Aguilar-Sanchez, Yuriana","roleDisplay":"VerfasserIn","given":"Yuriana","family":"Aguilar-Sanchez"},{"family":"Navarro-Garcia","given":"J. Alberto","display":"Navarro-Garcia, J. Alberto","roleDisplay":"VerfasserIn","role":"aut"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Ong, Isabelle","given":"Isabelle","family":"Ong"},{"given":"Luge","family":"Li","role":"aut","roleDisplay":"VerfasserIn","display":"Li, Luge"},{"given":"Amelie","family":"Paasche","role":"aut","display":"Paasche, Amelie","roleDisplay":"VerfasserIn"},{"display":"Abu-Taha, Issam","roleDisplay":"VerfasserIn","role":"aut","family":"Abu-Taha","given":"Issam"},{"family":"Tekook","given":"Marcel A.","display":"Tekook, Marcel A.","roleDisplay":"VerfasserIn","role":"aut"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Bruns, Florian","given":"Florian","family":"Bruns"},{"role":"aut","display":"Zhao, Shuai","roleDisplay":"VerfasserIn","given":"Shuai","family":"Zhao"},{"given":"Markus","family":"Kamler","role":"aut","roleDisplay":"VerfasserIn","display":"Kamler, Markus"},{"roleDisplay":"VerfasserIn","display":"Shen, Ying H.","role":"aut","family":"Shen","given":"Ying H."},{"display":"Chelu, Mihail G.","roleDisplay":"VerfasserIn","role":"aut","family":"Chelu","given":"Mihail G."},{"role":"aut","roleDisplay":"VerfasserIn","display":"Li, Na","given":"Na","family":"Li"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Dobrev, Dobromir","given":"Dobromir","family":"Dobrev"},{"display":"Wehrens, Xander H. T.","roleDisplay":"VerfasserIn","role":"aut","family":"Wehrens","given":"Xander H. T."}]} | ||
| SRT | |a KEEFEJOSHUMACROPHAGE6202 | ||