2018 Frontiers in Anesthesia Research Award $750,000

Wei Chao, MD, PhD, FAHA
The Dean’s Endowed Professor in Anesthesiology
Vice-Chair for Translational Research, Department of Anesthesiology
Associate Director, Shock Trauma Anesthesiology Research Center
University of Maryland School of Medicine
Baltimore, MD

Dr. Chao’s Research

Extracellular RNA, inflammation, and sepsis

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Cardiovascular collapse induced by cardiac dysfunction and profound vasodilatation represents a main feature of septic shock and contributes to its high mortality. Dysregulated innate immune response to pathogen components and endogenous host danger molecules proves to be deleterious in sepsis. We have discovered that host cellular RNAs are released into the blood during sepsis and that circulating host RNA is closely associated with sepsis severity in animals. miRNA array identifies six miRNAs that are elevated during sepsis; four of them (miR-34a, -122, -145, -146a) induce marked innate immune activation in immune cells, cardiomyocytes, and in intact animals. The over goal of this proposal is to determine the role of ex-miRNAs in host innate immune activation and in cardiac bioenergetic dysfunction in sepsis. The proposal is based on the following 3 hypotheses: 1) that host miRNAs are released from injured cells and play an important role in innate immune activation and cardiac dysfunction in sepsis, 2) that ex-miRNAs act through endosomal TLR7 signaling, 3) that pharmacological blockade of miRNAs after polymicrobial infection will attenuate innate immune activation and offer cardiac and survival benefit in sepsis. In Aim 1, we will determine the function and mechanism of plasma exosomes and ex-miRNAs in mediating innate immune responses in sepsis. In Aim 2, we will define the impact of ex-miRNAs to sepsis-induced cardiac bioenergetic dysfunction. In Aim 3, through a series of proof-of-concept pre-clinical studies, we will determine the therapeutic efficacy of synthetic anti-miR oligonucleotide inhibitors to modulate organ inflammation, organ injury, and mortality in sepsis. This proposal addresses a unique function of endogenous ex-miRNAs in host innate immunity and organ dysfunction with a significant implication to sepsis pathogenesis, treatment, and miRNA biology.

Related Publications

Enhanced loading of functional miRNA cargo via pH-gradient modification of extracellular vesicles.
Jeyaram A, Lamichhane TN, Wang S, Dahal E, Kronstadt SM, Levy D, Parajuli B, Knudsen D, Chao W, Jay SM.

Based on their identification as physiological nucleic acid carriers in humans and other organisms, extracellular vesicles (EVs) have been explored as therapeutic delivery vehicles for DNA, RNA, and other cargo.

Toll-like receptor 2 and 7 mediate coagulation activation and coagulopathy in murine sepsis.
Williams B, Neder J, Cui P, Suen A, Tanaka K, Zou L, Chao W.

Sepsis is a life-threatening condition often manifested as marked inflammation and severe coagulopathy. Toll-like receptors (TLRs) play a pivotal role in inflammation, organ dysfunction, and mortality in animal sepsis…

Toll-like Receptor 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis.
Jian W, Gu L, Williams B, Feng Y, Chao W, Zou L.

Sepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis…

Circulating Plasma Extracellular Vesicles from Septic Mice Induce Inflammation via MicroRNA- and TLR7-Dependent Mechanisms.
Xu J, Feng Y, Jeyaram A, Jay SM, Zou L, Chao W.

We have previously reported that a group of host cellular microRNAs (miRNAs; miR-34a-5p, miR-122-5p, miR-145-5p, miR-146a-5p, miR-210-3p) are released into the blood during sepsis, some of which are capable of inducing complement activation, cytokine production, and leukocyte migration. Extracellular vesicles (EVs) have been proposed as vehicles for extracellular miRNA-mediated intercellular communication. However, the biological function of plasma EVs and the associated miRNAs in sepsis are largely unknown…

Complement factor B is the downstream effector of Toll-like receptors and plays an important role in a mouse model of severe sepsis.
Zou L, Feng Y, Li Y, Zhang M, Chen C, Cai JY, Gong Y, Wang L, Thurman J, Wu X, Atkinson JP, Chao W.

Severe sepsis involves massive activation of the innate immune system and leads to high mortality. Previous studies have demonstrated that various types of Toll-like receptors (TLRs) mediate a systemic inflammatory response and contribute to organ injury and mortality in animal models of severe sepsis…

Myocardial ischemia induces a rapid activation of innate immune signaling via cardiac heat-shock protein 60 and Toll-like receptor 4.
Li Y, Feng Y, Chen H, Zou L, Si R, Wang E, Zhang M, Warren S, Sosnovik D, Chao W.

Innate immune response after transient ischemia is the most common cause of myocardial inflammation and may contribute to injury, yet the detailed signaling mechanisms leading to such a response are not well understood. Herein we tested the hypothesis that myocardial ischemia activates interleukin receptor-associated kinase-1 (IRAK-1), a kinase critical for the innate immune signaling such as that of Toll-like receptors (TLRs), via a mechanism that involves heat shock proteins (HSPs) and TLRs…

Role of extracellular RNA and TLR3-Trif signaling in myocardial ischemia-reperfusion injury.
Chen C, Feng Y, Zou L, Chen HH, Cai JY, Xu JM, Sosnovik DE, Chao W.

Toll-like receptor 3 (TLR3) was originally identified as the receptor for viral RNA and represents a major host antiviral defense mechanism. TLR3 may also recognize extracellular RNA (exRNA) released from injured tissues under certain stress conditions. However, a role for exRNA and TLR3 in the pathogenesis of myocardial ischemic injury has not been tested. This study examined the role of exRNA and TLR3 signaling in myocardial infarction (MI), apoptosis, inflammation, and cardiac dysfunction during ischemia-reperfusion (I/R) injury.

Cardiac RNA induces inflammatory responses in cardiomyocytes and immune cells via Toll-like receptor 7 signaling.
Feng Y, Chen H, Cai J, Zou L, Yan D, Xu G, Li D, Chao W.

We have recently reported that extracellular RNA (exRNA) released from necrotic cells induces cytokine production in cardiomyocytes and immune cells and contributes to myocardial ischemia/reperfusion injury. However, the signaling mechanism by which exRNA exhibits its pro-inflammatory effect is unknown. Here we hypothesize that exRNA directly induces inflammation through specific Toll-like receptors (TLRs)…

Splenic RNA and microRNA mimics promote complement factor B production and alternative pathway activation via innate immune signaling.
Zou L, Feng Y, Xu G, Jian W, Chao W.

Complement factor B (cfB) is an essential component of the alternative pathway (AP) and plays an important role in the pathogenesis of polymicrobial sepsis. However, the mechanism leading to cfB production and AP activation during sepsis remains poorly understood. In this study, we found that plasma cell-free RNA was significantly increased following cecal ligation and puncture (CLP), an animal model of polymicrobial sepsis, and was closely associated with sepsis severity…

Extracellular microRNAs induce potent innate immune responses via TLR7/MyD88-dependent mechanisms.
Feng Y, Zou L, Yan D, Chen H, Xu G, Jian W, Cui P, Chao W.

Tissue ischemia, such as transient myocardial ischemia, leads to release of cellular RNA including microRNA(miRNA) into the circulation and extracellular (ex-) space, but the biological function of the ex-RNA is poorly understood. We recently reported that cardiac RNA of both human and rodent origins induced cytokine production and immune cell activation…

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