Fc receptor γ-chain activation via hOSCAR induces survival and maturation of dendritic cells and modulates Toll-like receptor responses

Blood ◽  
2005 ◽  
Vol 105 (9) ◽  
pp. 3623-3632 ◽  
Author(s):  
Estelle Merck ◽  
Blandine de Saint-Vis ◽  
Mathieu Scuiller ◽  
Claude Gaillard ◽  
Christophe Caux ◽  
...  
Keyword(s):  
T Cells ◽  
Fc Receptor ◽  
Poly I:C ◽  
Toll Like Receptor ◽  
Phosphatidylinositol 3 Kinase ◽  
Monocyte Chemoattractant Protein 1 ◽  
Polycytidylic Acid ◽  
Extracellular Signal ◽  
Chemokine Ligand ◽  
Human Osteoclast

AbstractWe previously reported the characterization of human osteoclast-associated receptor (hOSCAR), a novel Fc receptor γ-chain (FcRγ)–associated receptor expressed by myeloid cells. Here we show that ligation of hOSCAR by specific antibodies promotes dendritic cell (DC) survival by an extracellular signal-regulated kinase (ERK)- and phosphatidylinositol 3-kinase (PI3K)–dependent pathway, linked to expression of the Bcl-2 and Bcl-xL antiapoptotic molecules. Crosslinking of hOSCAR leads to maturation of DCs, as demonstrated by up-regulation of maturation markers, decrease in dextran uptake capacity, and secretion of immunesystem effectors such as interleukin-8 (IL-8)/CXC chemokine ligand 8 (CXCL8), IL-12 p40, monocyte chemoattractant protein-1 (MCP-1)/chemokine receptor ligand 2 (CCL2) and macrophage-derived chemokine (MDC)/CCL22. Stimulation of hOSCAR acts in conjunction with the Toll-like receptor (TLR) ligands, lipopolysaccharide (LPS), R-848, and polyinosinic-polycytidylic acid (poly(I:C)), to increase the expression of maturation markers, and to modulate cytokine release. A PI3K-dependent up-regulation of IL-10 release is observed with all the TLR ligands used, whereas regulation of IL-12 production is variable depending on the TLR stimulated. hOSCAR engagement on DCs did not significantly increase the proliferation of naive T cells; however, when co-incubated with TLR ligands, an enhanced proliferation was observed. The percentage of interferon (IFN)–γ–producing T cells is decreased when hOSCAR engagement is combined with LPS stimulation. Altogether, these data suggest that hOSCAR may modulate the responses of both innate resistance and adaptive immunity.

scholarly journals Toll-Like Receptor-3 Ligation-Induced Indoleamine 2, 3-Dioxygenase Expression in Human Trophoblasts

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4984-4992 ◽  
Author(s):  
Bo Wang ◽  
Kaori Koga ◽  
Yutaka Osuga ◽  
Ingrid Cardenas ◽  
Gentaro Izumi ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Conditioned Media ◽  
Poly I:C ◽  
Type I ◽  
Toll Like Receptor ◽  
Human Trophoblast ◽  
Double Stranded Rna ◽  
Indoleamine 2 ◽  
Polycytidylic Acid

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades an essential amino acid, tryptophan, and plays a role in inhibiting the proliferation of T cells and intracellular pathogens. Inhibiting IDO in mice leads to fetal rejection, suggesting its significance in establishing pregnancy. Toll-like receptor 3 (TLR-3) is a key component of the innate immune system that recognizes viral double-stranded RNA and triggers immune reactions by producing type I interferon. Using a human trophoblast cell culture system, we studied the effect of TLR-3 ligation on IDO expression and function by treating trophoblasts with polyinosinic-polycytidylic acid [poly(I:C)] (a synthetic double stranded RNA, which mimics viral RNA). Real-time PCR and Western blot analysis revealed that IDO mRNA and protein expression was significantly induced by poly(I:C). The activity of IDO was also increased by poly(I:C) given that the l-kynurenine concentrations were elevated in conditioned media. Conditioned media from poly(I:C)-treated trophoblasts were found to inhibit the proliferation of human T cells significantly. Poly(I:C) was also shown to induce interferon (IFN)-β mRNA expression in trophoblasts. Recombinant human IFN-β increased IDO mRNA expression in trophoblasts more rapidly than poly(I:C). Pretreating with neutralizing antibody against IFN-β significantly suppressed IDO induction by poly(I:C). Collectively we have demonstrated that ligation of TLR-3 by poly(I:C) induces IDO expression in human first-trimester trophoblasts via an IFN-β-dependent pathway. These findings suggest that upon viral infection, trophoblasts induce IDO and in turn contribute to antimicrobial activity and maintenance of fetomaternal tolerance.

scholarly journals Interleukin-6 via Toll-Like Receptor 3 Signaling Attenuates the Expression of Proinflammatory Chemokines in Human Podocytes

2021 ◽  
Vol 46 (2) ◽  
pp. 207-218
Author(s):  
Hidenori Umetsu ◽  
Shojiro Watanabe ◽  
Tadaatsu Imaizumi ◽  
Tomomi Aizawa ◽  
Koji Tsugawa ◽  
...  
Keyword(s):  
Rna Interference ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Toll Like Receptor ◽  
Induced Expression ◽  
Inflammatory Reactions ◽  
Monocyte Chemoattractant Protein 1 ◽  
Polycytidylic Acid ◽  
Tlr3 Signaling

<b><i>Background:</i></b> Although toll-like receptor 3 (TLR3) signaling is involved in the development of certain chronic kidney diseases, the specific molecular mechanisms underlying inflammatory reactions via activation of TLR3 signaling in human podocytes remain unclear. Interleukin (IL)-6 is a pleiotropic cytokine associated with innate and adaptive immune responses; however, little is known about the implication of IL-6 via the activation of regional TLR3 signaling in the inflammatory reactions in human podocytes. <b><i>Methods:</i></b> We treated immortalized human podocytes with polyinosinic-polycytidylic acid (poly IC), an authentic viral double-stranded RNA, and assessed the expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), and C-C motif chemokine ligand 5 (CCL5) using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. To further elucidate the poly IC-induced signaling pathway, we subjected the cells to RNA interference against IFN-β and IL-6. <b><i>Results:</i></b> We found that the activation of TLR3 induced expression of IL-6, MCP-1, CCL5, and IFN-β in human podocytes. RNA interference experiments revealed that IFN-β was involved in the poly IC-induced expression of IL-6, MCP-1, and CCL5. Interestingly, IL-6 knockdown markedly increased the poly IC-induced expression of MCP-1 and CCL5. Further, treatment of cells with IL-6 attenuated the expression of CCL5 and MCP-1 mRNA and proteins. <b><i>Conclusion:</i></b> IL-6 induced by TLR3 signaling negatively regulates the expression of representative TLR3 signaling-dependent proinflammatory chemokines in human podocytes.

Abstract 095: CD74 Deficient Mice are Resistant to Toll-Like Receptor-Induced Preeclampsia

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Mohamad Hatahet ◽  
Olga Y Gasheva ◽  
Valorie L Chiasson ◽  
Piyali Chatterjee ◽  
Kelsey R Bounds ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Endothelial Dysfunction ◽  
Mhc Class Ii ◽  
Immune Cells ◽  
Immune Cell ◽  
Class Ii ◽  
Poly I:C ◽  
Hypertensive Disorder ◽  
Toll Like Receptor

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by vascular endothelial dysfunction and excessive immunity and inflammation. Activation of the dsRNA receptor Toll-like receptor 3 (TLR3) or the ssRNA receptor TLR7 elicits a pregnancy-dependent PE-like syndrome in mice by inducing a pro-inflammatory immune response. CD74 (MHC Class II invariant chain) acts as a chaperone for MHC Class II surface expression on immune cells during antigen presentation and is cleaved into Class II-Associated Invariant Peptide (CLIP) following polyclonal activation of immune cell TLRs. The presence of CLIP in the groove of MHC Class II prevents T cell-dependent death leading to persistent immune cell activation. We hypothesized that genetic deletion of CD74 and subsequent depletion of CLIP on immune cells prevents TLR-induced immune responses and the development of PE in mice. Pregnant WT and CD74 KO mice were given i.p. injections of normal saline (P), poly I:C (TLR3 agonist; P-PIC), or R837 (TLR7 agonist; P-R837) on gestational days 13, 15, and 17 and euthanized on day 18. P-PIC and P-R837 WT mice had significantly increased splenic levels of pro-inflammatory CD3+/gd T cells and plasma levels of the gd T cell-derived cytokines IFNg, TNFa, and IL-17 compared to P WT mice whereas P-PIC and P-R837 CD74 KO mice had significantly increased anti-inflammatory CD3+/gd T cells and no significant increases in plasma IFNg, TNFa, and IL-17 levels. P-PIC and P-R837 CD74 KO mice did not develop the hypertension (gd17 SBP in mmHg: P WT=102±3, P CD74 KO=100±3, P-PIC WT=147±4*, P-PIC CD74 KO=95±3, P-R837 WT=133±2*, P-R837 CD74 KO=97±1; *p<0.05 vs. P WT), endothelial dysfunction, proteinuria, or placental necrosis seen in P-PIC and P-R837 WT mice. In conclusion, CD74 is crucial for the development of TLR-induced PE-like symptoms in mice and CD74/CLIP depletion may be a promising therapeutic target for women with PE.

scholarly journals Autophagy Suppresses Toll-Like Receptor 3-Mediated Inflammatory Reaction in Human Epidermal Keratinocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Xue Mei Li ◽  
Kyung Eun Jung ◽  
Su Hyuk Yim ◽  
Dong Kyun Hong ◽  
Chang Deok Kim ◽  
...  
Keyword(s):  
Inflammatory Reaction ◽  
Skin Diseases ◽  
Poly I:C ◽  
Epidermal Keratinocytes ◽  
Toll Like Receptor ◽  
Inflammatory Skin Diseases ◽  
Human Epidermal Keratinocytes ◽  
Strong Light ◽  
Polycytidylic Acid ◽  
Inflammatory Skin

Autophagy, one mechanism of programmed cell death, is fundamental to cellular homeostasis. Previous studies have identified autophagy as a novel mechanism by which cytokines control the immune response. However, its precise role in immune-related inflammatory skin diseases such as psoriasis remains unclear. Thus, this study explored the functional role of autophagy in psoriatic inflammation of epidermal keratinocytes. Strong light chain 3 immunoreactivity was observed in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model, and it was readily induced by polycytidylic acid (poly (I:C)), which stimulates Toll-like receptor 3 (TLR3), in human epidermal keratinocytes in vitro. Rapamycin-induced activation of autophagy significantly reduced poly (I:C)-induced inflammatory reaction, whereas, inhibition of autophagy by 3-methyladeine increased that. Our results indicate that the induction of autophagy may attenuate TLR3-mediated immune responses in human epidermal keratinocytes, thus providing novel insights into the mechanisms underlying the development of inflammatory skin diseases including psoriasis.

scholarly journals Toll-Like Receptor 2-Dependent Extracellular Signal-Regulated Kinase Signaling in Mycobacterium tuberculosis-Infected Macrophages Drives Anti-Inflammatory Responses and Inhibits Th1 Polarization of Responding T Cells

2015 ◽  
Vol 83 (6) ◽  
pp. 2242-2254 ◽  
Author(s):  
Edward T. Richardson ◽  
Supriya Shukla ◽  
David R. Sweet ◽  
Pamela A. Wearsch ◽  
Philip N. Tsichlis ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Erk Signaling ◽  
Toll Like Receptor ◽  
Content Type ◽  
Extracellular Signal ◽  
Toll Like Receptor 2 ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Th1 Polarization

Mycobacterium tuberculosissurvives within macrophages and employs immune evasion mechanisms to persist in the host. Protective T helper type 1 (Th1) responses are induced, and the immune response in most individuals is sufficient to restrictM. tuberculosisto latent infection, but most infections are not completely resolved. As T cells and macrophages respond, a balance is established between protective Th1-associated and other proinflammatory cytokines, such as interleukin-12 (IL-12), interferon gamma (IFN-γ), and tumor necrosis factor alpha, and anti-inflammatory cytokines, such as IL-10. The mechanisms by whichM. tuberculosismodulates host responses to promote its survival remain unclear. In these studies, we demonstrate thatM. tuberculosisinduction of IL-10, suppression of IL-12, and inhibition of class II major histocompatibility complex (MHC-II) molecules in infected macrophages are all driven by Toll-like receptor 2 (TLR2)-dependent activation of the extracellular signal-regulated kinases (ERK). Elimination of ERK signaling downstream of TLR2 by pharmacologic inhibition with U0126 or genetic deletion ofTpl2blocks IL-10 secretion and enhances IL-12 p70 secretion. We demonstrate thatM. tuberculosisregulation of these pathways in macrophages affects T cell responses to infected macrophages. Thus, genetic blockade of the ERK pathway inTpl2−/−macrophages enhances Th1 polarization and IFN-γ production by antigen-specific CD4+T cells responding toM. tuberculosisinfection. These data indicate thatM. tuberculosisand its potent TLR2 ligands activate ERK signaling in macrophages to promote anti-inflammatory macrophage responses and blunt Th1 responses against the pathogen.

scholarly journals The p85 Subunit of Phosphatidylinositol 3-Kinase Associates with the Fc Receptor γ-Chain and Linker for Activitor of T Cells (LAT) in Platelets Stimulated by Collagen and Convulxin

1998 ◽  
Vol 273 (51) ◽  
pp. 34437-34443 ◽  
Author(s):  
Jonathan M. Gibbins ◽  
Stephen Briddon ◽  
Adam Shutes ◽  
Martine J. van Vugt ◽  
Jan G. J. van de Winkel ◽  
...  
Keyword(s):  
T Cells ◽  
Fc Receptor ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals Innate immune responses through Toll-like receptor 3 require human-antigen-R-mediated Atp6v0d2 mRNA stabilization

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mohd Izwan Bin Zainol ◽  
Takumi Kawasaki ◽  
Warunthorn Monwan ◽  
Motoya Murase ◽  
Takuya Sueyoshi ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Poly I:C ◽  
Type I ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Mrna Stabilization ◽  
Human Antigen R ◽  
Polycytidylic Acid ◽  
Endosomal Acidification

AbstractToll-like receptor 3 (TLR3) recognizes double-stranded RNA derived from virus and its synthetic analogue, polyinosinic–polycytidylic acid [poly(I:C)]. Upon poly(I:C) binding, TLR3 activates transcription factors to express inflammatory cytokines and type I interferon. TLR3 is located in the endosomes and its recognition of poly(I:C) and activation of downstream signaling is regulated by endosomal acidification. However, the mechanism of post-transcriptional regulation in TLR3-mediated innate responses remains unclear. Here, we focused on Human antigen R (HuR, also known as ELAVL1) that recognizes and binds to the 3′ untranslated regions (3′UTRs) of target mRNAs, thereby protecting them from mRNA degradation, and found that HuR-deficient murine macrophage cells showed significantly reduced Ifnb1 mRNA expression after poly(I:C) stimulation. HuR-deficient cells also showed a marked reduction in the expression of Atp6v0d2 mRNA, which encodes a subunit of vacuolar-type H+ ATPase (V-ATPase), and therefore reduced endosomal acidification. HuR associated with the 3′UTR of Atp6v0d2 mRNA and the stability of Atp6v0d2 mRNA was maintained by its association with HuR. Taken together, our results suggest that HuR stabilizes Atp6v0d2 mRNA, which is required for the TLR3-mediated innate immune responses.

scholarly journals IFIT Proteins Are Involved in CXCL10 Expression in Human Glomerular Endothelial Cells Treated with a Toll-Like Receptor 3 Agonist

2020 ◽  
pp. 1-12
Author(s):  
Tadaatsu Imaizumi ◽  
Shun Hashimoto ◽  
Riko Sato ◽  
Hidenori Umetsu ◽  
Tomomi Aizawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Tetratricopeptide Repeats ◽  
Immune Reactions ◽  
Polycytidylic Acid ◽  
Glomerular Endothelial Cells ◽  
Chemokine Ligand ◽  
Human Glomerular Endothelial Cells ◽  
Novel Coronavirus

Introduction: Various viruses including a novel coronavirus (SARS-CoV-2) can infect the kidney. When viruses invade the glomeruli from the bloodstream, glomerular endothelial cells (GECs) initiate the innate immune reactions. We investigated the expression of interferon (IFN)-induced protein with tetratricopeptide repeats (IFIT) 1/2/3, antiviral molecules, in human GECs treated with a toll-like receptor (TLR) 3 agonist. Role of IFIT1/2/3 in the expression of C-X-C motif chemokine ligand 10 (CXCL10) was also examined. Methods: Human GECs were cultured and stimulated with polyinosinic-polycytidylic acid (poly IC), a synthetic TLR3 agonist. Real-time qPCR, Western blotting, and ELISA were used to examine the expression of IFIT1/2/3, IFN-β, and CXCL10. RNA interference against IFN-β or IFIT1/2/3 was also performed. Results: Expression of IFIT1/2/3 and CXCL10 was induced by poly IC in GECs. The inductions were inhibited by RNA interfering of IFN-β. Knockdown of IFIT1/2/3 decreased the CXCL10 expression. Knockdown of IFIT3 decreased the expression of IFIT1 and IFIT2 proteins. Conclusion: IFIT1/2/3 and CXCL10 were induced by poly IC via IFN-β in GECs. IFIT1/2/3 may increase the expression of CXCL10 which induces lymphocyte chemotaxis and may inhibit the replication of infected viruses. These molecules may play a role in GEC innate immune reactions in response to viruses.

scholarly journals The influence of CD40 ligation and interferon-γ on functional properties of human monocyte-derived dendritic cells activated with polyinosinic-polycytidylic acid

2011 ◽  
Vol 68 (4) ◽  
pp. 301-308 ◽  
Author(s):  
Ana Dragicevic ◽  
Tanja Dzopalic ◽  
Sasa Vasilijic ◽  
Dragana Vucevic ◽  
Biljana Bozic ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Poly I:C ◽  
Peripheral Blood Mononuclear ◽  
Th1 Response ◽  
Polycytidylic Acid ◽  
Polyinosinic Polycytidylic Acid ◽  
Stimulation Of

Background/Aim. Ligation of a Toll-like receptor (TLR) by specific TLR agonists is a powerful tool for maturation induction of monocyte-derived dendritic cells (MoDCs). Studies so far have shown that the treatment of dendritic cells (DCs) with a TLR3 ligand, polyinosinic-polycytidylic acid [Poly(I:C)], may be an appropriate activation agent for obtaining mature MoDCs, competent to prime effective immune responses. However, little is known about how subsequent interaction of MoDCs with T cell-derived stimuli, such as CD40 or interferon-? (IFN-?), modulates MoDC functions. Therefore, this problem was the main objective of this study. Methods. Immature MoDCs were prepared by cultivation of monocytes from peripheral blood mononuclear cells with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4 for 5 days. After that, maturation was induced by the treatment of these cells with Poly(I:C) for 2 days. At day 6, immature MoDCs and Poly(I:C)-activated MoDCs were incubated either with CD40 ligand (L)-transfected J558 cells or IFN-? for additional 24 hours. Cytokine production was measured by ELISA and FlowCytomix Human T helper Th1/Th2 11plex. Allostimulatory capability of MoDCs was tested using an allogeneic mixed leukocyte reaction (MLR) assay. Results. Immature MoDCs showed a moderate potential for stimulation of proliferation of CD4+ T cells, which was enhanced by the treatment with Poly(I:C). Ligation of CD40 or treatment with IFN-? of immature or Poly(I:C)-treated MoDCs significantly up-regulated their allostimulatory activity. MoDCs matured in the presence of Poly(I:C) up-regulated the production of IL- 12 and IL-10, which was followed by increased levels of IFN- ? and decreased levels of IL-5 in co-cultures with allogeneic CD4+ T cells. Ligation of CD40 on immature MoDCs upregulated the production of IL-12 and IL-23 which was accompanied by increased secretion of IFN-? in co-culture. Stimulation of CD40 on Poly(I:C)-treated MoDCs significantly enhanced the production of IL-12, IL-23 and IL-10. However, such treated MoDCs decreased the production of IFN-? and IL-10 and up-regulated the secretion of IL-17. Immature MoDCs treated with IFN-? up-regulated IL-12, but lowered the production of IL-5 and IL-17 by CD4+ T cells. Treatment of Poly(I:C)-activated MoDCs with IFN-? down-regulated the production of IL-12 and up-regulated IL- 10 by these cells and increased/decreased the levels of IL-10/ IFN-?, respectively, in co-culture with CD4+ T cells. Conclusion. Treatment with Poly(I:C) or ligation of CD40 on immature MoDCs induces maturation of these cells into a phenotype that supports Th1 response. Activation of CD40 on Poly(I:C)-treated MoDCs shifts the immune response towards Th17. Treatment of immature MoDCs with IFN-? down-regulated Th2 and Th17 responses. However, addition of IFN-? to Poly(I:C)-activated MoDCs down-regulated Th1 response and promote T regulatory mechanisms. Each of these results may have functional and therapeutic implications.

scholarly journals Activation of Toll-like receptor 3 amplifies mesenchymal stem cell trophic factors and enhances therapeutic potency

2012 ◽  
Vol 303 (10) ◽  
pp. C1021-C1033 ◽  
Author(s):  
Michalis Mastri ◽  
Zaeem Shah ◽  
Terence McLaughlin ◽  
Christopher J. Greene ◽  
Leah Baum ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Growth Factor ◽  
Mesenchymal Stem Cell ◽  
Trophic Factors ◽  
Poly I:C ◽  
Functional Improvement ◽  
Toll Like Receptor ◽  
Polycytidylic Acid ◽  
Therapeutic Benefits

Clinical trials of bone marrow mesenchymal stem cell (MSC) therapy have thus far demonstrated moderate and inconsistent benefits, indicating an urgent need to improve therapeutic efficacy. Although administration of sufficient cells is necessary to achieve maximal therapeutic benefits, documented MSC clinical trials have largely relied on injections of ∼1 × 106 cells/kg, which appears too low to elicit a robust therapeutic response according to published preclinical studies. However, repeated cell passaging necessary for large-scale expansion of MSC causes cellular senescence and reduces stem cell potency. Using the RNA mimetic polyinosinic-polycytidylic acid [poly(I:C)] to engage MSC Toll-like receptor 3 (TLR3), we found that poly(I:C), signaling through multiple mitogen-activated protein kinase pathways, induced therapeutically relevant trophic factors such as interleukin-6-type cytokines, stromal-derived factor 1, hepatocyte growth factor, and vascular endothelial growth factor while slightly inhibiting the proliferation and migration potentials of MSC. At the suboptimal injection dose of 1 × 106 cells/kg, poly(I:C)-treated MSC, but not untreated MSC, effectively stimulated regeneration of the failing hamster heart 1 mo after cell administration. The regenerating heart exhibited increased CD34+/Ki67+ and CD34+/GATA4+ progenitor cells in the presence of decreased inflammatory cells and cytokines. Cardiac functional improvement was associated with a ∼50% reduction in fibrosis, a ∼40% reduction in apoptosis, and a ∼55% increase in angiogenesis, culminating in prominent cardiomyogenesis evidenced by abundant distribution of small myocytes and a ∼90% increase in wall thickening. These functional, histological, and molecular characterizations thus establish the utility of TLR3 engagement for enabling the low-dose MSC therapy that may be translated to more efficacious clinical applications.

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