Laboratory of Innate Immunity & Inflammation Biology


 

Liwu Li, PhD, FAHA
Endowed College of Science Faculty Fellow Professor of Inflammation Biology and Immunology
lwli@vt.edu
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,

Director, GBCB (Genetics, Bioinformatics & Computational Biology)

 

Innate Immune Memory Dynamics: Mechanistic Principles & Translational Applications in Inflammation Therapeutics

Our team studies the fundamental processes of innate immune memory and inflammation dynamics related to health and disease. We have pioneered signal-strength and duration dependent innate memory dynamics such as sustained low-grade inflammation, tolerance, exhaustion and resolution of monocytes and neutrophils. Our integrated experimental and computational analyses reveal key mechanistic principles of innate immune memory. Our translational studies reveal crucial significance of distinct innate memory dynamics during the pathogenesis of diverse acute and chronic diseases such as sepsis and atherosclerosis.

Low-grade inflammation memory during the pathogenesis of atherosclerosis Through integrated approaches that combine mechanistic and complementary functional examinations, we characterized monocytes with low-grade inflammatory memory features shared among mice and humans. Mechanistically, we defined the disruption of homeostatic resolution as the fundamental principle for the generation of sustained low-grade inflammation memory. We defined that the unique signaling adaptor TRAM(TICAM2) serves as an indispensable gatekeeper for initiating and sustaining low-grade inflammation memory by disrupting pexophagy. We demonstrated that the persistence of low-grade inflammatory monocytes contributes to the pathogenesis of atherosclerosis.

Innate exhaustion memory during sepsis Innate leukocytes are rewired during sepsis into a prolonged exhaustion state with the paradigm of pathogenic inflammation and immune suppression, which subjects the host to compromised defense to secondary infections as well as elevated risks for multi-organ inflammation and damage. Our group defined exhausted monocytes with the depletion of key metabolic fuel NAD+, initiated by TRAM related molecular circuitries. We first defined that exhausted monocytes can be generated by repetitive challenges with high dose endotoxin. The generation of exhaustion memory is responsible for long-term complications following the initial bout of septic insult.  

Therapeutically, we are interested in developing approaches that can restore cellular homeostasis. We defined that chemical rejuvenation of peroxisome via 4-PBA or genetic deletion of TRAM adaptor can effectively reprogram innate leukocytes into active resolving states, capable of propagating innate homeostasis and reducing inflammatory disease pathogenesis. We identified resolving monocytes and neutrophils characterized by elevated CD200R and reduced TRAM expression in both murine and human systems. Translational relevance during the pathogenesis and treatment of atherosclerosis, sepsis, cancer, and related inflammatory diseases are being examined using transgenic animal models as well as human blood samples.

Ongoing studies include biochemical, molecular as well as functional studies of innate immune memory dynamics in response to damage/danger signals with varying strength and duration under the setting of either acute or inflammatory conditions. Key intertwined players such as TRAM, TOLLIP, and IRAK-M are being examined in directing intra-cellular signaling circuitries involved in innate polarization and reprogramming dynamics. Our biochemical analyses reveal Tollip as a homeostatic molecule facilitating autophagy completion through interacting with PIP lipids. Sustained low-grade inflammatory signals disrupt Tollip function and compromises innate homeostasis.

 

Selected Publications:

For publications since 2002 click here.

Lin R, Wang J, Wu Y, Yi Z, Zhang Y, Li L*. (2023) Resolving neutrophils due to TRAM deletion renders protection against experimental sepsis. Inflamm Res. 72(8):1733-1744.

Yi Z, Geng S, Li L*. (2023) Comparative analyses of monocyte memory dynamics from mice to humans. Inflamm Res . 72(8):1539-1549.

Wang J, Wu Y, Lin R, Zhang Y, Li L*. (2023) TRAM deletion attenuates monocyte exhaustion and alleviates sepsis severity. Front Immunol. 14:1297329.

Geng S, Lin R, Wu Y, Wang J, Li L*. (2023) Modulation of Innate Immune Memory Dynamics by Subcellular Reactive Oxygen Species. Antioxid Redox Signal. 39(16-18):1027-1038.

Lin R, Yi Z, Wang J, Geng S, Li L*. (2022) Generation of resolving memory neutrophils through pharmacological training with 4-PBA or genetic deletion of TRAM. Cell Death Dis.13(4):345.

Naler L, Hsieh Y, Geng S, Zhou Z, Li L*, Chang Lu. (2022) Epigenomic and transcriptomic differences between low-grade inflammation and severe exhaustion in LPS-challenged murine monocytes. Nature Communications Biology. 5(1):102.

Pradhan K, Yi Z, Geng S, Li L* (2021) Development of Exhausted Memory Monocytes and Underlying Mechanisms. Frontiers in Immunology. 12:778830.

Geng S, Zhang Y, Yi Z, Lu R, Li L*. (2021) Resolving monocytes generated through TRAM deletion attenuate atherosclerosis. JCI Insight 6(20):e149651

Chin AL, Jiang S, Jang E, Niu L, Li L, Jia X, Tong R.(2021) Implantable optical fibers for immunotherapeutics delivery and tumor impedance measurement. Nature Communications 12(1):5138.

Geng S, Li L*. (2021) Differential training of innate leukocytes getting compartmentalized. J Leukoc Biol . doi: 10.1002/JLB.4CE0821-421.

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