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Inflammation and Human Diseases

       Inflammation underlies a variety of human diseases such as obesity, diabetes, cardiovascular and neurodegenerative diseases, arthritis and cancer. Together, these diseases constitute a major challenge to the well being of modern human society. Understanding the fundamental mechanisms of inflammation may provide rationales for designing novel interventions to treat these maladies. Autoinflammatory diseases are an emerging family of illness, characterized by dysregulation of innate immune responses. Studies of these hereditary human disorders have provided invaluable insight into basic cellular and molecular mechanisms of the innate immune regulation and have contributed significantly to the development of novel therapies for common human inflammatory diseases. My long term goal is to understand the underlying mechanisms of autoinflammatory diseases and to apply knowledge from such studies to develop novel treatment of inflammatory human diseases. Our recent studies of one such disease, namely mevalonate kinase deficiency, has allowed us to unravel the unexpected connection between the mevalonate pathway, a fundamental metabolic pathway and toll like receptor (TLR)-mediated phosphatidyl inosital 3(PI3)-kinase signaling. These exciting new discoveries will greatly advance our knowledge of innate immune signaling and regulation and may provide clues for new interventions of a variety of human diseases.


    Inflammation is orchestrated by cytokines in order to resolve infection or tissue damage. However, dysregulation of the production of those cytokines may cause diseases such as autoinflammation. Production of these cytokines is usually triggered by pathogen- or damage- associated molecular patterns (PAMPs or DAMPs). Engagement of innate immune receptors such as toll like receptors (TLRs) and/or Nod like receptors (NLRs) with PAMPs or DAMPs leads to the activation of a cascade of signal transduction events and eventually, the transcription of genes coding for proinflammatory cytokines such as TNFα, IL-1β, IFNβ, IL-12, IL-10 and IL-6. Coordinated action of these and other cytokines dictates the outcome of an inflammatory response.

     Among these cytokines, IL-1β and the closely related IL-18 are atypical in that they are synthesized as non-functional precursors. While synthesis of pro-IL-1β is usually triggered by TLR ligands (signal 1), maturation and secretion of these cytokines depends on the assembly and activation of inflammasomes (signal 2). Central to the function of inflammasomes is activation of caspase-1. Caspase-1 is synthesized as an inactive zymogen. Assembly of inflammasomes induces autocatalytic processing of procaspase-1 into its active form, which is then capable of cleaving the pro-IL-1β family members into mature, biologically active cytokines. Studies of human autoinflammatory diseases have elucidated that mutations in genes encoding inflammasome components that lead to spontaneous activation of inflammasomes, can cause server pathological consequences such as that in Cold-induced Autoinflammatory Periodic Fever syndrome (CAPS). Studies of these diseases have greatly improved our understanding of the molecular mechanisms of inflammasome activation and have lead to the tremendous success of anti-IL-1 biologics in treating not only autoinflammatory diseases but also common inflammatory disease such as gout arthritis.

    The mevalonate pathway is a fundamental pathway leading to the biosynthesis of cholesterols. One rate -limiting enzyme, namely 3-hydroxyl-3-methylglutaryl Co-enzyme A Reductase (HMGCR), has been targeted by statins, the specific inhibitors of HMGCR, for treatment of hypercholesterolemia. Over the past two decades, statins have dramatically decreased the mortality and morbidity in patients suffering from cardiovascular disease. Mevalonate kinase catalyzes the phosphorylation of mevalonate, an essential step of cholesterol biosynthesis, that is one step downstream of HMGCR. Mevalonate Kinase Deficiency (MKD, OMIM#610377) is a rare autosomal recessive, metabolic autoinflammatory disease caused by mutations in the gene encoding mevalonate kinase (MVK). Missense mutations in MVK often result in a dramatic decrease of MVK enzyme activity. MKD patients manifest with inflammatory phenotypes such as periodic fever, splenomegaly, inflammatory skin lesions, and arthritis. Recent clinical studies demonstrated that proinflammatory cytokines, particularly IL-1β, play important roles in the pathology. MKD patients display higher IL-1β and TNFα levels in their circulation in comparison to healthy controls. More strikingly, the inflammatory symptoms can be cured by anti-IL-1 or anti-TNFα biologics in most of the MKD patients. Those clinical observations suggest that mevalonate pathway may be important for the regulation of innate immune responses. The focus of my study is to understand the underlying mechanisms of inflammation through studying those autoinflammatory diseases.

      In addition to its role in the biosynthesis of cholesterol, the mevalonate pathway also produces isoprenoids. More specifically, it produces geranylgeranyl pyrophosphate which may serve as a substrate for protein geranylgeranylation. Protein geranylgeranylation is catalyzed by the protein geranylgeranyl transferase (GGTase-I). A recent report has shown that protein geranylgeranylation plays a pivotal role in the regulation of  innate immune responses. Mouse macrophage deficient for GGTase-I are hyper activated in response to Toll-like receptor (TLR) ligands. In addition, mice with a specific deficiency of GGTases in myeloid cells develop erosive, inflammatory arthritis. These observations suggest that protein geranylgeranylation might be the missing link between the mevalonate pathway and the innate immune signaling network.

Our recent findings:

Using the GGTase-I deficient mouse model, we have discovered:
In the absence of protein geranylgeranylation, TLR-induced PI3K-AKT activation is severely compromised. As a consequence, this lead to increased GSK3β and inhibited mTOR activity.
In combination, changed activity of GSK3β and mTOR in GGTase-I deficient macrophages drives enhanced production of proinflammatory cytokines such as IL-6, TNFα, IL-12 and IL-23, in the mean time production of anti-inflammatory cytokines such as IL-10 and IFNβ  are inhibited.
Deficiency of GGTase-I also lead to spontaneous activation of inflammasomes upon TLR stimulation, a process that usually depends on a so-called second signal.
Hyperactivation of the proinflammatory pathway in GGTase-I KO cells is caused by compromised PI3K activation, since constitutively active PDK1 can reverse those inflammatory phenotypes in GGTase-I deficient cells.
Protein geranylgeranylation regulates TLR induced PI3K activation through Ras or Rho family small GTPases, well established substrate of protein prenylation.
Through an yet to be revealed mechanism, PI3K-AKT pathway negatively regulates inflammasome activation.


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