Laboratory of Innate Immunity & Inflammation Biology


Dr. Liwu Li
Professor of Inflammation Biology and Immunology
Phone: (540) 231-1433
Fax: (540) 231-4043
162 Life Science 1 Building, 907 Washington Street,
Blacksburg, Virginia 24061-0910
Biological Sciences, Medicine, & Biomedical Engineering,
GBCB (Genetics, Biotechnology & Computational Biology)


Molecular Signaling Circuits Modulating Innate Memory and Inflammation

Our research team seeks to unravel the dynamic circuitry that governs the balance of inflammatory responses at cellular and molecular levels. Specifically, our group is studying the novel establishment of innate immune memory. Our studies in the last two decades revealed that innate leukocytes can be skewed into distinct inflammatory; tolerant; or exhausted phenotype, depending upon the magnitude and duration of external stimulants. As a consequence, differential priming; tolerance and exhaustion would have profound impacts on the pathophysiology of both acute and chronic inflammatory diseases.

Subclinical endotoxemia in circulation is a significant health concern associated with the pathogenesis of diverse chronic inflammatory diseases. We identified that the polarization of low-grade inflammatory monocytes can be generated by persistent exposure to subclincial super-low dose endotoxin. The establishment of non-resolving low-grade inflammatory monocytes or neutrophils exacerbates the pathogenesis of both acute and chronic diseases such as sepsis and atherosclerosis.

At the molecular level, Toll-like receptor (TLR) proteins in immune cells can recognize a diverse array of microbial products and relay the signals through a serious of intracellular signaling components including the adaptors (e.g. MAL/MyD88, TRAM/TRIF, and Tollip) and interleukin-1 receptor-associated kinase (IRAK) family proteins (1, 2, M, and 4). Employing integrated experimental and computational approaches, we defined that competing intra-cellular dynamics among several interwoven pathways may tilt the innate leukocytes to diverse fates. With particular interest, we reported that the TRAM signaling circuit is preferentially involved in mediating the priming effect of subclinical super-low dose endotoxin.

We have found that Tollip can specifically bind with phosphatidylinositol-3-phosphate. This finding is the first of its kind showing selective binding of phophatidylinositde (PI) lipids by TLR intracellular adaptor molecules. PI lipids are differentially distributed within the intracellular membrane network, and play a pivotal role in the proper compartmentalization of signaling molecules and pathways. We demonstrated that Tollip dynamically shuttles among late endosome/lysosome and mitochondria, therefore modulating key cellular processes such as lysosome fusion with autophagosome and directing the dynamic polarization of innate immune cells. The competing circuits established between positive signals and negative signals make it possible for innate immune cells to be differentially activated into distinct states upon challenges with varying dosages of TLR stimulants.

Ongoing studies include detailed biochemical, molecular as well as functional studies of IRAK family kinases and TRAM, Tollip involved in the sensing of bacterial endotoxin (Lipopolysaccharide) by innate leukocytes under the setting of either acute (sepsis) or chronic (metabolic endotoxemia) inflammatory conditions. We are also interested in approaches that can restore cellular homeostasis. The involvements of non-resolving inflammatory leukocytes in the pathogenesis of atherosclerosis, sepsis, cancer, and related inflammatory diseases are being examined using transgenic animal models.

Selected Publications:

For publications since 2002 click here.

He X, et al (2021) LYSMD3: A mammalian pattern recognition receptor for chitin. Cell Reports. 36(3):109392

Geng S, Pradhan K, Li L (2021) Signal-Strength and History-Dependent Innate Immune Memory Dynamics in Health and Disease. Handbook of Experimental Pharmacology. doi: 10.1007/164_2021_485.

Pradhan K, Geng S, Zhang Y, Lin RC, Li L. (2021) TRAM-Related TLR4 Pathway Antagonized by IRAK-M Mediates the Expression of Adhesion/Coactivating Molecules on Low-Grade Inflammatory Monocytes. Journal of Immunology. 206 (12).

He et al. (2021) Deficiency of the novel high mobility group protein HMGXB4 protects against sepsis in mice. PNAS. 118(7):e2021862118.

Lee J, Geng S, Li S, Li L (2021) Single Cell RNA-Seq and Machine Learning Reveal Novel Subpopulations in Low-Grade Inflammatory Monocytes With Unique Regulatory Circuits. Frontiers in Immunology. 12:627036.

Lin R, Zhang Y, Pradhan K, Li L* (2020) TICAM2-related pathway mediates neutrophil exhaustion. Scientific Reports. 10(1):14397.

Casasanta MA et al. (2020) Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration. Science Signaling. 13(641):eaba9157

Geng S, Zhang Y, Lee C, Li L* (2109) Novel reprogramming of neutrophils modulates inflammation resolution during atherosclerosis. Science Advances. 5(2).

Zhang Y, Lee C, Geng S, Li L* (2109) Enhanced tumor immune surveillance through neutrophil reprogramming due to Tollip deficiency. Journal of Clinical Investigation Insight. 4(2):e122939.

Zhang Y, Geng S, Prasad GL, Li L* (2018) Suppression of Neutrophil Antimicrobial Functions by Total Particulate Matter From Cigarette Smoke. Front Immunol. 9:2274.

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. 293(31):12239-12247.

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. 104(3):535-541.

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. 46(12):1549-1563.

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.

Dynamic modulation of innate immune response by varying dosages of LPS in human monocytic cells. Morris, M, Gilliam E, Button J, Li L*. J Biol Chem. 2014. 289(31):21584-90.

Molecular and cellular mechanisms responsible for cellular stress and low-grade inflammation induced by super-low dose endotoxin. Baker B, Maitra U, Geng S, Li L*. J Biol Chem. 2014. 289:16262-16269.

Detecting intracellular translocation of native proteins quantitatively at the single cell level. Zhenning Cao, Shuo Geng, Liwu Li and Chang Lu. Chemical Science. 2014. 5: 2530-2535.

Molecular mechanisms responsible for the reduced expression of cholesterol transporters from macrophages by low-dose endotoxin. Maitra U, Li L*. Arterioscler Thromb Vasc Biol. 2013. 33(1):24-33.

Molecular mechanism responsible for the priming of macrophage activation. Deng H, Maitra U, Morris M, Li L*. J Biol Chem. 2013. 288(6):3897-906.

The ubiquitin ligase stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor foxp3. Chen Z, Barbi J, Bu S, Yang HY, Li Z, Gao Y, Jinasena D, Fu J, Lin F, Chen C, Zhang J, Yu N, Li X, Shan Z, Nie J, Gao Z, Tian H, Li Y, Yao Z, Zheng Y, Park BV, Pan Z, Zhang J, Dang E, Li Z, Wang H, Luo W, Li L, Semenza GL, Zheng SG, Loser K, Tsun A, Greene MI, Pardoll DM, Pan F, Li B. Immunity. 2013. 39(2):272-85.

Change in mononuclear leukocyte responsiveness in midpregnancy and subsequent preterm birth. Harper M, Li L, Zhao Y, Klebanoff MA, Thorp JM Jr, Sorokin Y, Varner MW, Wapner RJ, Caritis SN, Iams JD, Carpenter MW, Peaceman AM, Mercer BM, Sciscione A, Rouse DJ, Ramin SM, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Obstet Gynecol. 2013. 121(4):805-11.

Causes and consequences of low grade endotoxemia and inflammatory diseases. Glaros TG, Chang S, Gilliam EA, Maitra U, Deng H, Li L*. Front Biosci. 2013. 5:754-65

Potent suppression of arginase 1 expression in murine macrophages by low dose endotoxin. Surace MJ, Li L*. Am J Clin Exp Immunol. 2013. 2(1):117-23.

Molecular mechanisms responsible for the selective and low-grade induction of proinflammatory mediators in murine macrophages by lipopolysaccharide. Maitra U, Deng H, Glaros T, Baker B, Capelluto D, Li Z, Li L*. J Immunology. 2012. 189(2):1014-2.

Network topologies and dynamics leading to endotoxin tolerance and priming in innate immune cells. Fu Y, Glaros T, Zhu M, Wang P, Wu Z, Tyson JJ, Li L*, Xing J*. PLoS Comput Biol. 2012 May;8(5):e1002526. * Co-correspondence.

Molecular mechanisms and pathological consequences of endotoxin tolerance and priming. Morris M, Li L*. Arch Immunol Ther Exp. 2012 Feb;60(1):13-8.

Molecular mechanism underlying persistent induction of LCN2 by lipopolysaccharide in kidney fibroblasts. Glaros T, Fu Y, Xing J, Li L. PLoS One. 2012;7(4):e34633.

Low dose endotoxin induces inflammation by selectively removing nuclear receptors and activating C/EBP delta. Maitra U, Gan L, Chang S, Li L*. Journal of Immunology. 2011; 186: 447-4473.

The Tollip C2 domain exhibits broad preference to phosphoinositides. Ankem G, Mitra S, Sun F, Moreno A, Chutvirasakul B, Azurmendi H, Li L, Capelluto D. Biochemical Journal. 2011; 435: 597-608.

A Mathematical Model for the Reciprocal Differentiation of T Helper 17 Cells and Induced Regulatory T Cells. Hong T, Xing J, Li L, Tyson J. pLoS Computational Biology.  2011 Jul;7(7):e1002122.

Mathematical Modeling for the Pathogenesis of Alzheimer’s Disease. Ishwar Puri*, Li L*. pLOS ONE. 2010; 5(12):e15176.

Chafin C, Muse S, Hontecillas R, Bassaganya-Riera J, Caudell D, Shimp S, Rylander MN, Zhang J, Li L, Reilly C. (2010) Deletion of PPAR-γ in immune cells enhances susceptibility to antiglomerular basement membrane disease. Journal of Inflammation Research. 3:127-134.

Gan L, Li L*. (2010) Interleukin-1 Receptor-associated Kinase-1 (IRAK-1) functionally Associates with PKCepsilon and VASP in the Regulation of Macrophage Migration. Molecular Immunology. 47(6):1278-82.

Frisard MI, McMillan RP, Marchand J, Wahlberg KA, Wu Y, Voelker KA, Heilbronn L, Haynie K, Muoio B, Li L, Hulver MW (2010) Toll-like receptor 4 modulates skeletal muscle substrate metabolism. Am J Physiol Endocrinol Metab. 298(5):E988-98.

Vaughn T, Li L* (2010) Molecular mechanism underlying the inflammatory complication of leptin in macrophages. Molecular Immunology. 47: 2515-2518.

Peairs A, Dai R, Gan L, Shimp S, Rylander MN, Li L, Reilly CM. (2010) EGCG attenuates inflammation in MRL/lpr mouse mesangial cells. Cell Mol Immunol. 7: 123-132.

Maitra U, Singh N, Gan L, Ringwood L, Li L*. (2009) IRAK-1 contributes to LPS-induced ROS generation in macrophages by inducing NOX-1 transcription, Rac1 activation, and suppressing the expression of anti-oxidative enzymes. Journal of Biological Chemistry. 284(51):35403-11

Maitra U, Parks J, Li L*. (2009) . Molecular and Cellular Biology. 29(22):5989-97.

Maitra U, Chang S, Singh N, Li L*. (2009) Molecular Mechanism Underlying the Suppression of Lipid Oxidation during Endotoxemia. Molecular Immunology.47(2-3):420-5.

Maitra U, Davis S, Reilly CM, Li L. (2009) Differential regulation of Foxp3 and IL-17 expression in CD4 T helper cells by IRAK-1. Journal of Immunology. 182: 5763-5769.

Glaros T, Larsen M, Li L*. (2009) Inflammation, tissue damage and organ injury. Frontiers in Bioscience. 14: 3988-3993.

Peairs A, Radjavi A, Davis S, Li L, Ahmed A, Giri S, Reilly CM. (2009) Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells. Clin Exp Immunol. 156(3):542-51.

Su J, Zhang T, Tyson J, Li L*. (2009) The interleukin-1 receptor associated kinase M selectively inhibits the alternative, instead of the classical NFkB pathway. Journal of Innate Immunity. 1: 164-174.

Piao W, Song C, Chen H, Quevedo Diaz MA, Wahl LM, Fitzgerald KA, Li L, Medvedev AE. (2009) Endotoxin tolerance dysregulates MyD88- and Toll/IL-1R domain-containing adapter inducing IFN-{beta}-dependent pathways and increases expression of negative regulators of TLR signaling. Journal of Leukocyte Biology. Aug 5. [Epub ahead of print]

Maitra U, Baglin S, Li L*. (2009) Inflammatory Signaling networks as Targets for Pharmacological Intervention of Chronic Diseases.  Current Signal Transduction Therapy.  4:103-110.

Li L, Chen SF, Liu Y. (2009) MAP kinase phosphatase-1, a critical negative regulator of the innate immune response. Int J Clin Exp Med. 2(1):48-67

Wang D, Fasciano S, Li L*. (2008) The Interleukin-1 Receptor Associated Kinase 1 contributes to the regulation of NFAT. Mol. Immunol.  45:3902-3908.

Ringwood L, Li L*. (2008) The involvement of the interleukin-1 Receptor-Associated Kinases (IRAKs) in cellular signaling networks controlling inflammation.Cytokine. 42:1-7.

Xie Q, Gan L, Wang J, Wilson I, Li L*. (2007) Loss of the innate immunity negative regulator IRAK-M leads to enhanced host immune defense against tumor growth. Mol Immunol. 44:3453-3461.

Su J, Xie Q, Wilson I, Li L*. (2007) Differential regulation and role of interleukin-1 receptor associated kinase-M in innate immunity signaling.Cell Signal. 19:1596-1601.

Lakoski SG, Li L, Langefeld CD, Liu Y, Howard TD, Brosnihan KB, Xu J, Bowden DW, Herrington DM. (2007) The association between innate immunity gene (IRAK1) and C-reactive protein in the Diabetes Heart Study. Exp Mol Pathol. 82:280-283.

Su J, Richter K, Zhang C, Gu Q, Li L*. (2007) Differential regulation of interleukin-1 receptor associated kinase 1 (IRAK1) splice variants.Mol Immunol.2007 Feb;44(5):900-5.

Fasciano S, Li L*. (2006) Intervention of Toll-like receptor-mediated human innate immunity and inflammation by synthetic compounds and naturally occurring products. Curr Med Chem. 13(12):1389-95.

Paulsen MT, Starks AM, Derheimer FA, Hanasoge S, Li L, Dixon JE, Ljungman M. (2006) The p53-targeting human phosphatase hCdc14A interacts with the Cdk1/cyclin B complex and is differentially expressed in human cancers. Mol Cancer. 2006 Jun 19;5:25.

Sun J, et. al. (2006) Interactions of sequence variants in interleukin-1 receptor-associated kinase4 and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 15(3):480-5.

Sun J, Zheng S, Chang B, Li L, Li G, Liu W, Turner AR, Meyers DA, Isaacs EB, Xu J, Grönberg H. (2005) Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) are associated with prostate cancer risk. Journal of the National Cancer Institute. 97: 525-532.

Chan C, Li L, McCall CE, Yoza B. (2005) Endotoxin Tolerance Disrupts Chromatin Remodeling and NF-kB Transactivation at the IL-1beta Promoter. Journal of Immunology . 175: 461-468.

Li T, Hu J, and Li L*. (2004) Regulation of Tollip by lipopolysaccharide in THP-1 cells. Molecular Immunology. 41 (1):85-92.

Huang Y, Li T, Sane DC, Li L*. (2004) IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced interleukin-10 gene expression. J Biol Chem. 279, 51697-703.

Jacinto R, Hu J, Hartung T, McCall CE, Li L*. (2002) LPS and LTA-induced tolerance and cross-tolerance: Distinct alterations in IRAK. Journal of Immunology. 168: 6136-6141.

Moors M, Li L, Mizel S. (2001) Bacterial FliC protein activates macrophages via TLR-IRAK mediated pathway. Infection and Immunity. 69, 4424-4429.

Learn C, Boger S, Li L*, McCall CE. (2001) Phosphortidyl-inositol-3-phosphate kinase selectively controls IL-1 RA protein production in tolerant cells. J Biol Chem. 276, 20234-9.

Li L* , Coursat S, Hu J, McCall C. (2000) Characterization of Interleukin-1 receptor associated kinase in normal and tolerant cells. Journal of Biological Chemistry.275, 23340-45.

Liwu Li , Jack Dixon. (2000) Form, function, and regulation of protein tyrosine phosphatases and their involvement in human diseases. Seminars in Immunology. 12 (1), 75-84.

* Correspondence