Research LetterCardiologyInflammation
Open Access | 
10.1172/jci.insight.196153
Small noncoding RNA TY2 enhances efferocytosis and improves outcomes in a mouse model of sepsis
Alessandra Ciullo, Xaviar M. Jones, Hiroaki Komuro, Liang Li, Anh Nguyen, Eduardo Marbán, and Ahmed Gamal-Eldin Ibrahim
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Address correspondence to: Alessandra Ciullo, Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, California 90048, USA. Email: alessandra.ciullo@cshs.org.
Find articles by Ciullo, A. in: PubMed | Google Scholar
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Address correspondence to: Alessandra Ciullo, Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, California 90048, USA. Email: alessandra.ciullo@cshs.org.
Find articles by Jones, X. in: PubMed | Google Scholar
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Address correspondence to: Alessandra Ciullo, Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, California 90048, USA. Email: alessandra.ciullo@cshs.org.
Find articles by Komuro, H. in: PubMed | Google Scholar
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Address correspondence to: Alessandra Ciullo, Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, California 90048, USA. Email: alessandra.ciullo@cshs.org.
Find articles by Li, L. in: PubMed | Google Scholar
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Address correspondence to: Alessandra Ciullo, Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, California 90048, USA. Email: alessandra.ciullo@cshs.org.
Find articles by Nguyen, A. in: PubMed | Google Scholar
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Address correspondence to: Alessandra Ciullo, Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, California 90048, USA. Email: alessandra.ciullo@cshs.org.
Find articles by Marbán, E. in: PubMed | Google Scholar
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Address correspondence to: Alessandra Ciullo, Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, California 90048, USA. Email: alessandra.ciullo@cshs.org.
Find articles by Gamal-Eldin Ibrahim, A. in: PubMed | Google Scholar
Published January 29, 2026 - More info
JCI Insight. 2026;11(5):e196153. https://doi.org/10.1172/jci.insight.196153.
© 2026 Ciullo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
To the Editor: Extracellular vesicles contain bioactive noncoding RNAs (1), including yREX3, a small Y RNA that enhances macrophage efferocytosis by suppressing protein interacting with C kinase 1 (Pick1) (2). Here, we report the development of TY2, an exomer (3) bioinspired by yREX3. TY2 includes locked nucleic acids (Figure 1A) and a point mutation (uracil to adenine, yREX33’UtoA) that increased Pick1 downregulation (Figure 1B) to yield yREX33’UtoA 3 alternated, renamed TY2 by convention (1) (Supplemental Figure 1A). TY2 was more resistant to RNase degradation (Figure 1C) and enhanced efferocytosis more potently compared with yREX3 (Figure 1D and Supplemental Figure 1B). Rats fed (4) TY2 or yREX3 (3.25 ng/g) after reperfusion had smaller infarcts by histology or circulating cardiac troponin I 48 hours after myocardial infarction (MI) (Figure 1, E–G). Thus, relative to yREX3, TY2 is more stable and at least bioequivalent. To test TY2 in sepsis, we induced cecal ligation and puncture (CLP) in 6-week-old C57BL/6 mice (5) (Figure 1H). Seven days after ligation, mice receiving TY2 showed improved survival (Figure 1I) and greater weight loss, largely due to reduced ascites (Supplemental Figure 1, C and D). Spleen weight was significantly reduced in TY2-treated mice compared with sham mice, indicating reduced inflammation (Supplemental Figure 1, E and F). Serum lactate and aspartate aminotransferase (6) were also attenuated by TY2 (Supplemental 1, G and H). Blood glucose levels decreased in all septic animals compared with sham mice (6) (Supplemental Figure 1I). Echocardiography 1 day after CLP (before treatment) and at endpoint (day 7) revealed reduced cardiac dysfunction (Figure 1J and Supplemental Figure 1J) and remodeling (Figure 1K) with TY2 compared with vehicle. Bacterial counts at endpoint were lower in hearts and lungs of TY2-treated mice (cf. vehicle; Figure 1, L and M). In vitro, macrophages from bone marrow take up inactivated E. coli particles conjugated with a fluorophore as a reporter of efferocytosis. Exposure to TY2 increased efferocytosis relative to vehicle (Figure 1, N and O; cf. Supplemental Figure 1, B and D); the effect was independent of animal sex (Supplemental Figure 2, A and B) and time dependent (Supplemental Figure 2C). In vivo, SMAD3 phosphorylation was increased in hearts from CLP mice exposed to TY2, consistent with increased efferocytotic activity (Figure 1, P and Q) and the protective role of PSMAD3 in mitigating inflammation in sepsis (7). Indeed, mice receiving TY2 showed decreased levels of inflammatory cytokines Tnfa, Il1b, and Il10; a trend for a decrease in Il6 in heart samples; and, in the lungs, decreased Il1b (Supplemental Figure 1K), consistent with less severe sepsis (6). Thus, TY2 mimics yREX3 mechanistically while being more stable, making it worth testing in settings such as sepsis where enhanced efferocytosis may be beneficial.
Figure 1TY2 is protective in a rat model of MI and in a model of cecal ligation and puncture–induced sepsis. (A) Schematic of two-step structure activity screening using yREX3 as a template. Locked nucleic acids are shown in red. (B) Pick1 downregulation screening of synthetic candidates. (C) Stability of yREX3 and TY2 exposed to increasing concentrations of RNAse R. (D) Efferocytosis assay showing uptake of DiD-labeled dead rat cardiomyocytes by rat macrophages at 48 hours. (E–G) TTC staining showing infarct size (E and F) and ELISA of circulating cardiac troponin I (cTnI) (G) in rats with MI receiving yREX3 or TY2 i.v. or orally by gavage after reperfusion. (H) Cecal ligation and puncture–induced (CLP-induced) polymicrobial sepsis model was induced at day 0. Numbers represent days. (I) Kaplan-Meier curve showing survival of treatment groups (sham, n = 5; vehicle, n = 8; TY2, n = 9). (J) Echocardiographic measurement of cardiac function (fractional shortening [FS] %) at day 1 and day 7. (K) Left ventricular internal diameter (LVID; mm). (L) Bacterial burden in tissue measured in hearts (L) and lungs (M) using qPCR of bacterial 16S. (N and O) Assessment of bacterial (E. coli) clearance by bone marrow–derived macrophages exposed to vehicle or TY2. Scale bar: 200 μm. (P and Q) PSMAD3 and CD68 expression in heart sections of mice receiving vehicle or TY2 at 72 hours. Scale bar: 100 μm. Data are presented as mean ± SEM. Dots represent single animals. Statistical analysis of two groups was by Student’s unpaired 2-tailed t test, with 95% CI (C, N, and Q) and that of 3 or more groups was by 1-way ANOVA with Tukey’s (D, J, and K) or Dunnett’s (B, F, G, L, and M, vs. Veh) post test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.
For detailed methods, information regarding sex as a biological variable, statistics, study approval, author contributions, data availability statement, and acknowledgments, see the supplemental materials.
