Inflammation is a process to resolve infection, repair damaged tissues and maintain host homeostasis. However, dysfunction of the innate and adaptive immune system and out of control of inflammation may cause loss of function of critical organs that results in severe disease conditions. In addition to the prototypes of autoimmune inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematous, there is an etiological element of inflammation in almost all of the chronic diseases such as cardiovascular diseases, metabolic diseases, malignancy and neuro-degenerative diseases. Together, these chronic diseases create enormous healthcare burden on the human society. Understanding the fundamental mechanisms of inflammation holds the key to the discovery of innovative interventions for these chronic human diseases. Studies in the past have shown that rare human autoinflammatory diseases ( where individuals’ innate immune system are dysregulated owing to in-born errors) provided unique opportunities to elucidate the fundamental mechanisms of inflammation.
The mevalonate pathway is a fundamental metabolic pathway for cholesterol biosynthesis. Although hypercholesterolemia causes atherosclerosis, cholesterol itself is a vital component of cellular membranes and serves as the precursor of a variety of important molecules essential for host development and survival. This is highlighted by the observation that defects of the key enzymes of the mevalonate pathway lead to embryonic or perinatal lethality. For decades, clinicians as well as scientist have been puzzled by the fact that deficiency of the mevalonate kinase, an essential enzyme in the cholesterol biosynthesis pathway, causes severe inflammatory phenotypes in human patients. More interestingly, the inflammatory phenotypes in these patients can be treated with IL-1 blockade. These observations suggest that there are crosswalks between the cholesterol biosynthesis pathway and the innate immune signaling network. Combining a mouse model and human patients samples, work in our laboratory has revealed this missing link, namely protein geranylgeranylation. In addition to cholesterols, the mevalonate pathway also produces geranylgeranyl pyrophosphate (GGPP), an isoprenoid intermediates. Protein geranylgeranylation uses GGPP as a substrate for protein post-translational modifications. Protein geranylgeranylation controls Phosphatidyl Inositol-3-(OH) Kinase (PI3K) activation induced by Toll-like Receptors (TLRs). Deficiency of the mevalonate kinase creates a shortage of GGPP, therefore inhibits protein geranylgeranylation, which in turn compromises PI3K activation and as a result rampant proinflammatory cytokine production (Acula, et al. Nature Immunology June 2016 accepted).
The mevalonate pathway has been successfully targeted by statins, inhibitors of the 3-hyroxyl-3-methylglutamyl Co-Enzyme A Reductase (HMGCR). Owing to the outstanding clinical safety profile and immune-modulatory capacity, there are tremendous interests in applying statins to treat other diseases such as multiple sclerosis (MS), a diseases caused by autoimmunity to human brain. However, a few clinical trials failed to establish firmly a positive effect of statins use in controlling disease progression in MS patients. We lack the in depth understanding of the role of the mevalonate pathway in the pathogenesis and disease progression in MS to rationally design strategies to target the mevalonate pathway. On going work in our lab is aiming at studying how protein geranylgeranylation may alter cytokine milieu, antigen presentation processes and cognate T-cell and antigen presenting cell interaction that eventually lead to the differentiation of the pathogenic auto-responsive IL-17 and IFNg-producing T cell subsets. These T cell subsets are believed to play pivotal roles in the pathogenesis of MS.
Statins have achieved tremendous success in preventing cardiovascular diseases. However, statin use does come with a price. One of the side effects is increased incidences of type diabetes mellitus. Millions of patients around the globe depends on statins to control they cholesterol level and to prevent CVDs. We are interested in studying how suppression of the mevalonate pathway may cause metabolic diseases. We are collaborating with experts of metabolomics to elucidate the underlying pathogenic mechanisms.
Another ongoing research in our lab is how the mevalonate pathway controls osteoclastogenesis. The Nitrogen containing bisphosphonates (NBPs) have been used successfully to treat osteoporosis for more than 40 years. NBPs inhibits the function of farnesyl pyrophosphate synthase, another essential enzyme in the mevalonate pathway. However, how mevalonate pathway controls osteoclastogenesis remains obscure. Using a mouse model with protein geranylgeranylation deficiency, we are dissecting the detailed molecular mechanisms how inflammatory conditions may alter osteoclastogenesis pathway and the advantage as well as shortfalls of NBPs in treating osteoporosis.
Cholesterols and other intermediates of the mevalonate pathway plays an essential role in cell structure and survival. Genetic lesions disturbing cholesterol biosynthesis often lead to deformation of the embryo and the fetal brain. This is because the developing fetus and fetal brain are secluded by blood –placental barrier and the blood-brain barrier that circulating cholesterol in the form of Low Density Lipoproteins (LDL) cannot penetrate. Therefore, the developing fetus and brain depends on de novo biosynthesis of cholesterols once the placental/blood or brain-blood barrier are formed. A large part of the brain is composed of cholesterols, including the insulation myelin sheath. We are also investigating how limit of cholesterol biosynthesis leads to intrauterine growth restriction and developmental defect.
Research on the mevalonate pathway have been awarded Nobel Prizes twice, one in 1964 to Drs. Konrad Block and Feodor Lynen, and most recently to Joe Goldstein and Michael Brown 1985. Yet, we are still just at the beginning to understand how this fundamental pathway regulates other signaling networks and how itself is controlled by other signaling circuits. Studying of this pathway and its interaction with other signaling circuits of the body will continue to provide us new clues for fighting human diseases.