Professor of Inflammation Biology and Immunology, Department of Biological Sciences
Program Focus
Programming of Innate Immune Memory in Chronic Inflammatory Diseases
Our research group reveals a striking association between skewed innate immunity and the pathogenesis of inflammatory diseases. We first systematically documented the novel “memory” of innate immune response and its underlying immunological mechanisms. Conventionally, it was thought that only acquired immunity has memory, and that innate immunity only serves as a rudimentary first-line of defense with no memory. However, both basic and clinical studies allude to the notion that innate immunity also has memory. This is classically represented by the paradigm of “priming” and “tolerance” manifested in innate monocytes and macrophages when challenged with sequential dosages of inflammatory mediators such as microbial lipopolysaccharide (LPS), hormones, or cytokines. This bears critical relevance in human health and diseases. For example, Pre-conditioned innate immune systems by low dosages of microbial products may elicit a more robust defense toward subsequent infection. On the other hand, innate systems challenged with overwhelming dosages of microbial products or cytokines would try to dampen host responses in order to prevent excessive collateral inflammatory damages to the host. In terms of “sterile” inflammatory conditions without live microbes, priming and tolerance of innate immunity also determine the fate of inflammation such as acute “resolving” inflammation, versus chronic “non-resolving” inflammation. Non-resolving inflammation is the key culprit underlying the pathogenesis of human inflammatory diseases such as sepsis, atherosclerosis, fibrosis, diabetes, cancer and Alzheimer’s disease. Our research will continue to define the dynamic circuitries responsible for the programming of innate leukocytes. Potential drug targets will be identified for the treatment of chronic diseases. Promising compounds that may intervene or re-program innate memory will be tested.
Selected Publications
Kowalski E, Geng S, Rahtes A, Lu R, Li L* (2018) Toll-interacting protein differentially modulates HIF1α and STAT5-mediated genes in fibroblasts. J Biol Chem. In press.
Rahtes A, Geng S, Lee C, Li L* (2018) Cellular and Molecular Mechanisms Involved in the Resolution of Innate Leukocyte Inflammation. Journal of Leukocyte Biology. In Press.
Lee C, Zhang Y, Geng S, Li L* (2017) Dynamic programming of innate leukocytes in health and disease. J Leukocyte Biology. Invited review. 102(3):719-726.
Kowalski L, Li L* (2017) Toll-interacting Protein and Low-grade Inflammation. Frontiers in Immunology. 8:511. doi: 10.3389/fimmu.2017.00511.
Chen K, Yuan R, Geng S, Zhang Y, Ran T, Kowalski, Liu J, Li L*. (2017) Toll-interacting protein deficiency promotes neurodegeneration via impeding autophagy completion in high-fat diet-fed ApoE-/- mouse model. Brain, Behavior & Immunity. 59:200-210.
Chen K, Yuan R, Zhang Y, Geng S, Li L* (2017) Blockage of lipophagy due to Tollip deficiency exacerbates atherosclerosis and steatosis. Journal of American Heart Association 6(4) e004078.
The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis. Geng S, K Chen, R Yuan, L Peng, U Maitra, N Diao, C Chen, Y Zhang, Y Hu, C Qi, S Pierce, W Ling, H Xiong & Liwu Li. 2016 Nature Communications. 7:13436.
Molecular mechanisms that underlie the dynamic adaptation of innate monocyte memory to varying stimulant strength of TLR ligands. Ruoxi Yuan, Shuo Geng and Liwu Li. Frontiers in Immunology. 2016. doi: 10.3389/fimmu.2016.00497
Reprogramming macrophage orientation by microRNA 146b targeting transcription factor IRF5. Peng L, Zhang H, Hao Y, Xu F, Yang J, Zhang R, Lu G, Zheng Z, Cui M, Qi C, Chen C, Wang J, Hu Y, Wang D, Pierce S, Li L, Xiong H. 2016 eBioMedicine.
Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic colitis. Diao N, Zhang Y, Chen K, Yuan R, Lee C, Geng S, Kowalski E, Guo W, Xiong H, Li M, Li L. Sci Rep. 6:34672.
Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection. (2016) Huang C, Jiang D, Francisco D, Berman R, Wu Q, Ledford JG, Moore CM, Ito Y, Stevenson C, Munson D, Li L*, Kraft M, Chu HW. (2016) Clin Exp Allergy. In press.
Dynamic modulation of innate immunity programming and memory. Yuan R, Li L (2016) Science China Life Science. Invited Review,59(1):38-43.
Subclinical-Dose Endotoxin Sustains Low-Grade Inflammation and Exacerbates Steatohepatitis in High-Fat Diet-Fed Mice. Guo H, Diao N, Yuan R, Chen K, Geng S, Li M, Li L. (2016) J Immunol. 196(5):2300-8.
Low-grade inflammatory polarization of monocytes impairs wound healing. Yuan R, Geng S, Chen K, Diao N, Chu HW, Li L. (2016) J Pathology. 238(4):571-83
Alteration of lysosome fusion and low-grade inflammation mediated by super-low dose endotoxin. Baker B, Geng S, Chen K, Diao N, Yuan R, Xu X, Dougherty S, Stephenson C, Xiong H, Chu H, Li L*. J Biol Chem. 2015. 290(10):6670-8.
Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Lu G, Zhang R, Geng S, Peng L, Jayaraman P, Chen C, Xu F, Yang J, Li Q, Zheng H, Shen K, Wang J, Liu X, Wang W, Zheng A, Qi C, Si C, He J, Liu K, Lira S, Sikora A, Li L*, Xiong H*. (2015) Nature Communications. 6:6676. * Co-correspondence.
Super-low dose endotoxin pre-conditioning exacerbates sepsis mortality. Chen K, Geng S, Yuan R, Diao N, Upchurch Z, Li L*. eBioMedicine. 2015. 2(4):324-333.
Trehalose-mediated autophagy impairs the anti-viral function of human primary airway epithelial cells.Wu Q, Jiang D, Huang C, van Dyk LF, Li L, Chu HW. PLoS One. (2015) 10(4):e0124524.
Dynamic programing of innate leukocytes by bacterial endotoxin and its pathophysiological consequences. Morris M, Gilliams E, Li L*. Frontiers in Immunology. 2015 (Invited review).
A new innate sensor for an ancient molecular pattern. Li L. Sci China Life Sci. 2014. 57:1236-7.