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Our Research

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Immunoregulation of hepatic metabolism

It has been well appreciated for decades that obesity triggers a state of chronic inflammation in the liver that is associated with metabolic dysfunction. The connection between inflammation and metabolism has been suggested to involve the actions of proinflammatory cytokines secreted by infiltrating immune cells. However, anti-inflammatory strategies targeting cytokines have consistently proven to be ineffective at improving insulin action and metabolic function. Thus, the mechanism by which inflammatory factors directly trigger metabolic dysfunction remains an unanswered fundamental biological question. 

We have been interested in identifying the transcription factors and pathways that mediate the effects of inflammation on metabolism and have focused on members of the interferon regulatory factor (IRF) family. The nine mammalian IRFs have been implicated in almost every aspect of immunity, and IRF3 in particular, has been implicated in metabolic processes including adipogenesis and thermogenesis. Our lab was the first to define the role of IRF3 in liver metabolic function. By integrating the IRF3-dependent transcriptome and cistrome in mouse hepatocytes, we showed that IRF3 is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b, a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. We identified a previously unknown hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggested an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.


We are currently pursuing several lines of investigation related to the actions of IRF3, including: (a) What are the tissue-specific roles of IRF3 in macrophages (Kupffer cells)? (b) Is IRF3 required for the development of steatosis? (c) What are the critical downstream target genes of IRF3 in liver, and how do they impact metabolic function? (d) What are the key IRF3-mediated post-translational modifications (ISGylation) that influence hepatic metabolism?

Role of gap junction intercellular communication in liver disease

Cell–cell communication can be categorized by its dependency on contact. Contact-independent signaling is ideal for long-range communication whereas contact-dependent signaling is best suited for spatially localized rapid communication. Gap junction intercellular communication represents an elegant mechanism for enabling direct communication between neighboring cells. Gap junctions are assemblies of intercellular channels composed of connexin (Cx) proteins. A functional channel is formed when a hemichannel from one subset assembles with a hemichannel of the same subset from an adjacent cell. The resulting gap junctions directly connect the cytosol of the coupled cells, allowing the exchange of ions, nutrients, and secondary messengers for the maintenance of tissue homeostasis. In the liver however, the role of gap junction intercellular communication remains poorly understood.


Our lab showed that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of both acute and chronic liver injury. Inhibiting Cx32 gap junctions in the liver protected against drug-induced liver injury (DILI). We identified a small molecule inhibitor of Cx32 as a novel hepatoprotectant that phenocopies Cx32 deficient mice when co-administered with known hepatotoxic drugs, like acetaminophen. We also demonstrated that Cx32 deficiency protects against liver injury, inflammation, and fibrosis in three murine models of NAFLD. Using a histologically characterized cohort of 362 patients with NAFLD, we showed that hepatic Cx32 expression associates with NAFLD activity score. Lastly, we demonstrated that Cx32 deficiency also protects against alcohol-induced liver injury by limiting the intercellular spread of cGAS-derived cGAMP and IRF3 activation. Taken together, our lab established hepatic gap junctions as critical players in promoting liver disease, and developed a new therapeutic strategy for limiting liver injury.

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Innate immune sensing of DNA


Double-stranded DNA (dsDNA) derived from host, viral, or bacterial sources elicits a potent innate immune response by activating a TLR-independent cytosolic DNA sensor. We began investigating how dsDNA is sensed by eukaryotic cells in 2009. At that time the enigmatic cytosolic DNA sensor (now known as cGAS) had not yet been discovered. The signaling pathway downstream of cGAS, including STING, also remained a mystery.


We developed stable GFP reporters to study the complex spatiotemporal activation patterns of two key transcription factors in innate immunity: Nuclear factor-KappaB (NF-kB) and IRF3. We demonstrated that dsDNA-induced NF-kB activation is actually dependent on TNFa secretion, and that dsDNA stimulates TNFa secretion through activation of IRF3. We also showed that dsDNA stimulation induces the formation of multicellular colonies of IRF3-activated cells that collectively expressed more than 95% of critical secreted cytokines, including IFNb and TNFa. Gap junction communication was necessary for the formation of these IRF3 active colonies, and blocking gap junctions with genetic specificity limited the secretion of IFNb and TNFa, and the corresponding antiviral state. Our findings described a previously unknown intercellular signaling pathway triggered by cytosolic dsDNA sensing and provided evidence for the first time that gap junction communication is critical for the amplification of antiviral and inflammatory responses.

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