Cardiac RNA Induces Inflammatory Responses in Cardiomyocytes and Immune Cells via Toll-like Receptor 7 Signaling

Feng, Yan; Chen, Hongliang; Cai, Jiayan; Zou, Lin; Yan, Dan; Xu, Ganqiong; Li, Dan; Chao, Wei

doi:10.1074/jbc.m115.661835

Cited by 52 publications

(63 citation statements)

References 48 publications

(52 reference statements)

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“…Increased level of eRNA was demonstrated in bronchoalveolar lavage fluids of patients suffering from acute respiratory distress syndrome (ARDS)47. This eRNA may participate in ARDS pathogenesis by increasing permeability of epithelia-capillary barrier48, enhancing intraalveolar fibrin deposition22234749 and stimulating the production and release of proinflammatory cytokines2223262749. Here, we propose a novel function of eRNA, which promotes S. pneumoniae infection and the development of pneumonia, a well-described direct cause of ARDS50.…”

Section: Discussionmentioning

confidence: 98%

“…Extracellular nucleic acids were found to induce humoral and cellular immune responses during infection and to promote the formation of fibrin that entraps invading microbes202122. In particular, host-derived eRNA was reported to: i) enhance fibrin deposition by the activation of the contact phase pathway2223, ii) increase the adhesion and transmigration of leukocytes to and across the endothelium24, iii) and, augment the release of proinflammatory cytokines such as macrophage inflammatory protein-2, interleukin-1β, −6, −10, and tumor necrosis factor α from neutrophils, bone marrow-derived macrophages and endothelial cells24252627. However, the direct interaction of host-derived eRNA with pneumococcal surface, and the potential consequences of this process on bacterial tropism have not been addressed thus far.…”

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confidence: 99%

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Host-derived extracellular RNA promotes adhesion of Streptococcus pneumoniae to endothelial and epithelial cells

Zakrzewicz

Bergmann

Didiášová

et al. 2016

Sci Rep

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Streptococcus pneumoniae is the most frequent cause of community-acquired pneumonia. The infection process involves bacterial cell surface receptors, which interact with host extracellular matrix components to facilitate colonization and dissemination of bacteria. Here, we investigated the role of host-derived extracellular RNA (eRNA) in the process of pneumococcal alveolar epithelial cell infection. Our study demonstrates that eRNA dose-dependently increased S. pneumoniae invasion of alveolar epithelial cells. Extracellular enolase (Eno), a plasminogen (Plg) receptor, was identified as a novel eRNA-binding protein on S. pneumoniae surface, and six Eno eRNA-binding sites including a C-terminal 15 amino acid motif containing lysine residue 434 were characterized. Although the substitution of lysine 434 for glycine (K434G) markedly diminished the binding of eRNA to Eno, the adherence to and internalization into alveolar epithelial cells of S. pneumoniae strain carrying the C-terminal lysine deletion and the mutation of internal Plg-binding motif were only marginally impaired. Accordingly, using a mass spectrometric approach, we identified seven novel eRNA-binding proteins in pneumococcal cell wall. Given the high number of eRNA-interacting proteins on pneumococci, treatment with RNase1 completely inhibited eRNA-mediated pneumococcal alveolar epithelial cell infection. Our data support further efforts to employ RNAse1 as an antimicrobial agent to combat pneumococcal infectious diseases.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Host-derived extracellular RNA promotes adhesion of Streptococcus pneumoniae to endothelial and epithelial cells

Zakrzewicz

Bergmann

Didiášová

et al. 2016

Sci Rep

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“…55 In a recent report, however, it was demonstrated that cardiomyocytes responded to eRNA (isolated from cardiomyocytes or from heart tissue) especially in the presence of lipofectamine with by guest on May 11, 2018 http://circres.ahajournals.org/ Downloaded from the induction of inflammatory factors in a TLR7-MyD88-dependent manner. 56 Because these data were derived with the help of transfection agents, it remains to be established in which way eRNA can naturally gain access to endosomal TLR7 in the absence of such chemicals.…”

Section: Erna In Myocardial Infarction and I/r Injurymentioning

confidence: 99%

Extracellular Ribonucleic Acids (RNA) Enter the Stage in Cardiovascular Disease

Zernecke

Preissner

2016

Circulation Research

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Inflammatory and ischemic cardiovascular diseases, especially atherosclerosis and myocardial infarction, remain the number one cause of death in the Western world, whereas the therapeutic options currently available are still limited. Several recent findings have indicated that nucleic acids, particularly extracellular ribosomal RNA and micro-RNAs, significantly contribute to the adverse outcome of atherosclerosis, myocardial infarction, and other cardiovascular diseases. Extracellular RNAs act as novel danger-associated molecular pattern signals and potent cofactors in cardiovascular inflammation and thrombosis, particularly when accumulating in the extracellular space under tissue-damaging or pathological conditions. In this concise review article, the different entities of extracellular RNAs, their cellular sources, and their putative functional contribution to the pathogenesis of cardiovascular diseases will be discussed. In fact, it remains a tightrope walk for these polyanionic molecules outside cells to promote defense reactions on the one side but to provoke cardiovascular disease development on the other side, dependent on their concentration, the environmental conditions, and the cellular stimuli engaged. Thus, we will discuss the mechanisms and cellular responses by which extracellular RNAs operate between defense and disease. Finally, natural counteracting molecules, such as RNase1, will be focused on to elaborate their protective functions in the context of inflammatory and ischemic cardiovascular diseases with the possibility to apply them as novel interventional strategies.

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“…TLRs recognize both pathogen-associated molecular components [7, 8], such as lipopolysaccharide of gram-negative bacteria and peptidoglycan of gram-positive bacteria, and endogenous danger-associated molecular patterns, such as heat shock proteins and extracellular RNA [9–11]. To date, ten TLR family members in human and thirteen in mice have been identified [12].…”

Section: Introductionmentioning

confidence: 99%

Complement Factor B Production in Renal Tubular Cells and Its Role in Sodium Transporter Expression During Polymicrobial Sepsis*

Zou

Feng

et al. 2016

Critical Care Medicine

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Objectives Toll-like receptors (TLRs) and complement are two components of the innate immunity. Factor B (cfB) is essential for the alternative pathway (AP) of complement activation. We have recently reported that cfB is significantly up-regulated in the kidney and may contribute to acute tubular injury in an animal model of sepsis. The current study investigates the mechanisms responsible for the cfB up-regulation and its role in sodium transporter expression in tubular cells during sepsis. Design Animal study. Setting Laboratory investigation. Subjects C57BL/6 J wide-type (WT), cfB−/−, and Nfkb1tm1Bal p50−/− mice. Interventions Human proximal tubular cells (HK-2) and mouse tubular epithelial cells (MTECs) were stimulated with TLR agonists. Bay 11-7082 was used to block NF-κB pathway. AP activation was detected by C3 zymosan deposition. Polymicrobial sepsis was created by cecal ligation and puncture (CLP). Sodium transporter gene expression was determined by qRT-PCR. Measurements and Main Results The agonists for TLR4 (LPS) or TLR3 (poly I:C) induced a marked increase in cfB expression in HK-2 and MTECs both at gene and protein levels. The TLR1/2 agonist, Pam3cys, induced cfB production only in HK-2 cells, not MTEC. The TLR9 ligand, CpG, failed to induce cfB production either in HK-2 cells or MTEC. LPS/poly I:C-induced cfB up-regulation was blocked by Bay 11-7082, a potent inhibitor of NF-κB signaling, and in MTECs deficient in p50 subunit of NF-κB. Media from the LPS-treated MTEC cultures contained de novo synthesized cfB and led to functional AP activation. In a CLP model, WT septic mice had down-regulated expression of sodium transporters in the kidney compared with the sham. In comparison, cfB−/− mice or mice treated with anti-cfB displayed preserved levels of Na+/K+ ATPase-α1 following sepsis. Conclusions 1) TLR3/4 activation is sufficient to induce cfB production via NF-κB pathway and to enhance AP activation in the kidney tubular epithelial cells; 2) cfB may contribute to the down-regulation of certain sodium transporter expression during sepsis.

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Cardiac RNA Induces Inflammatory Responses in Cardiomyocytes and Immune Cells via Toll-like Receptor 7 Signaling

Cited by 52 publications

References 48 publications

Host-derived extracellular RNA promotes adhesion of Streptococcus pneumoniae to endothelial and epithelial cells

Host-derived extracellular RNA promotes adhesion of Streptococcus pneumoniae to endothelial and epithelial cells

Extracellular Ribonucleic Acids (RNA) Enter the Stage in Cardiovascular Disease

Complement Factor B Production in Renal Tubular Cells and Its Role in Sodium Transporter Expression During Polymicrobial Sepsis*

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