Toll-like receptors (TLRs) and oligomerization domain containing proteins (Nods) are two major pattern recognition receptors (PRR) involved in host defense against microbial pathogens. Recent evidence suggests that certain TLRs and Nods can be activated by endogenous molecules including saturated fatty acids leading to the induction of sterile inflammation. Chronic inflammation is considered as one of key pathological conditions leading to the development of many chronic diseases including atherosclerosis, cancer and insulin resistance. Results from epidemiological and genetic studies linked TLRs to risk modification of many chronic diseases. Then, dietary and pharmacological agents that can suppress PRR-mediated inflammation may have preventive efficacy for such chronic diseases.
Dr. Hwang’s group, for the first time, demonstrated that saturated fatty acids stimulate but polyunsaturated fatty acids (PUFAs) particularly n-3 PUFAs, inhibit TLR signaling pathways and the expression of target genes (J. Biol. Chem. 2001: J Lipid Res. 2003; J Biol. Chem 2004). Dr. Hwang’s subsequent work (J Immunology 2005) demonstrated that saturated and n-3 PUFAs reciprocally modulate dendritic cell functions and T-lymphocyte activation as a functional consequence of the reciprocal modulation of TLR-signaling pathways and target gene expression. These findings provided a conceptual foundation that dietary fatty acids can modulate TLR4-mediated chronic inflammation and consequent risk of chronic disease. In addition, the results from Dr. Hwang’s recent studies showed that certain plant polyphenols inhibit TLR4 and its target gene expression (Biochem Pharmacol 2006). It was also revealed that another pattern recognition receptor, Nods are also reciprocally modulated by saturated and n-3 PUFAs (J. Biol. Chem 2007). Dr. Hwang’s recent studies further delineated the mechanism as to how fatty acids modulate the activation of TLR4. There is no evidence that fatty acids can directly bind TLRs. Fatty acids modulate the activation of TLR4 by regulating dimerization and recruitment of the receptor into lipid rafts in a reactive oxygen species-dependent manner (J Biol Cem 2009). These findings define a new paradigm for the molecular mechanism by which dietary fatty acids regulate TLR4-mediated signaling pathways, target gene expression and cellular (immune) responses. TLR-mediated chronic inflammation can lead to increased risk of development and progression of many chronic diseases including atherosclerosis and insulin resistance. It is now recognized that TLRs and Nods are key pattern recognition receptors that can be activated by endogenous molecules leading to sterile inflammation. Therefore, Dr. Hwang’s research interest is focused in understanding how pattern recognition receptor-mediated sterile inflammation and risk of chronic disease can be modulated by what we eat with emphasis on dietary fatty acids and phytochemicals.