Laboratory of Innate Immunity & Inflammation Biology

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Dr. Liwu Li
Professor of Inflammation Biology and Immunology
lwli@vt.edu

Phone: (540) 231-1433
Fax: (540) 231-4043

Research Program in Inflammation

Virginia Tech, Biological Sciences
162 Life Science 1 Building, Washington Street,
Blacksburg, Virginia 24061-0910

 

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. Macrophages can be skewed into either an inflammatory or anergic phenotype, depending upon the magnitude of external stimulants. The dynamic balance among several interwoven pathways may tilt the macrophages to opposing directions. Similar paradigm occurs in T helper cells. The competing dynamics between these phenotypes eventually dictate the inflammatory environment and the outcome of disease pathogenesis.

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 interleukin-1 receptor-associated kinase (IRAK) family proteins (1, 2, M, and 4). Each IRAK member has unique regulation and role in modulating the inflammatory network in immune cells. We have demonstrated that IRAK-1 undergoes stimulus-dependent activation, sumoylation and nuclear translocation. In contrast to IRAK-4 and IRAK-2, IRAK-1 is dispensable for and not directly involved in the classical NFkB pathway. Instead, IRAK-1 contributes to the activation of ATF2 and C/EBPdelta. Furthermore, we observed that IRAK-1 also suppresses the activities of NFAT and nuclear receptors including RARa. Consequently, IRAK-1 participates in the differential activation of macrophages and T cells. IRAK-M, on the other hand, negatively regulates NFkB activation. The competing circuit established between IRAK-1 and IRAK-M makes it possible for innate immune cells to be either primed or tolerized by varying dosages of TLR stimulants.

We are also interested in the examination of signaling adaptor molecules involved in the inflammatory network such as Tollip. 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 can be inducibly translocated onto mitochondria, and participate in the dynamic polarization of innate immune cells.

Ongoing studies include detailed biochemical, molecular as well as functional studies of IRAK family kinases and Tollip involved in the sensing of bacterial endotoxin (Lipopolysaccharide) by host macrophages and T cells under the setting of either acute (sepsis) or chronic (metabolic endotoxemia) inflammatory conditions. The involvement of IRAK and Tollip proteins in the pathogenesis of sepsis, injury, atherosclerosis and related inflammatory diseases are being examined using transgenic animal models.

Selected Publications:

For publications since 2002 click here.

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. In press.

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.

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.

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.

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.