Bing Li | |
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Occupation(s) | Immunologist, researcher and academic |
Academic background | |
Education | Ph.D. in Immunology |
Alma mater | Jiangsu University School of Medicine Southeast University School of Medicine Peking University Health Science Center |
Academic work | |
Institutions | University of Louisville University of Minnesota University of Iowa |
Bing Li is an immunologist,researcher,and academic. He is an Endowed Professor for Cancer Immunology, [1] a professor of Pathology at the University of Iowa, [2] and the Director of Iowa Cancer and Obesity Initiative. [3] He is also the founder of BMImmune Inc. [4]
Li's research has focused on how FABP4 and FABP5 regulate metabolism and signaling in leukocytes. His work has linked FABPs to diseases like obesity,chronic inflammation,and cancer risk and development,while also identifying clinical applications through targeted FABP activity modification. [5]
Li has been appointed as the University Scholar by the University of Louisville, [6] Endowed Professor in Cancer Immunology Research by the University of Iowa and was featured as a Spotlight Investigator by Nutrition Frontiers,a publication of the Nutritional Science Research Group (NSRG),NCI,NIH. He serves as the Guest Editor of Tumor Microenvironment for the journal Cancers , [7] and has been an Editorial Board Member for the Journal of Allergy,and BMC Immunology. [8]
In 1994,Li graduated from Jiangsu University School of Medicine and went on to serve as a Research Assistant there. In 2001,he completed his M.S. in Immunology from Southeast University School of Medicine and earned a Ph.D. in Immunology from Peking University Health Science Center in 2004. Subsequently,he was appointed as a Postdoctoral Associate at the University of Louisville,followed by a Postdoctoral Fellow position in the Department of Microbiology and Immunology at the same university from 2007 to 2010. [9]
Li was appointed as an Assistant Professor at the Hormel Institute,University of Minnesota in 2011. In 2016,he was appointed as an Associate Professor in the Department of Microbiology and Immunology at the University of Louisville. [10] Since 2021,he has been serving as a professor of pathology, [1] and an Endowed Professor in Cancer Immunology at the Department of Pathology of the University of Iowa. [11]
Li has been appointed as the Director of Iowa Cancer and Obesity Initiative at the University of Iowa [3] and serves as a Steering Committee Member of the NCI MeDOC Consortium and Nutritional Group Chair for NCI MeDOC Consortium Program at NIH/NCI. [12]
Li has conducted research on the role of fatty acid binding proteins (FABPs),particularly FABP4 and FABP5,in chronic inflammation,obesity,cancer development,and their influence on immune cell functions relevant to obesity-related diseases. In 2020,he presented a SnapShot outlining FABPs' functions,which was published in the cell biology journal Cell . [13]
Li's research primarily explores the functions of Fatty Acid-Binding Proteins (FABPs) in obesity,chronic inflammation,and cancer development,with a specific focus on the complex relationship between obesity and 13 different types of cancers and the unexplored molecular mechanisms underlying these associations. His research indicates FABP4,also known as adipose FABP(A-FABP),as a new player linking obesity-increased risk of breast cancer and possibly other cancers. [14] More specifically,he did research on how FABP4 drives obesity-associated cancer risk through several main mechanisms. While conducting a study on circulating FABP4 which are traditionally thought to be an intracellular protein facilitating fatty acid transport and storage,he showed that obesity increases FABP4 secretion from the adipose tissue. Furthermore,he demonstrated how elevated circulating FABP4 directly binds to cancer cells,promoting the expression of aldehyde dehydrogenase 1 (ALDH1),a hallmark of breast cancer stem cells. Thus,circulating FABP4 mediates cancer risk and progression by enhancing cancer stemness. [15] Subsequently,his research on Intracellular FABP4 investigated how FABP4 besides being expressed in adipocytes are highly expressed in certain subsets of macrophages which are very heterogeneous in tumor stroma,some with antitumor activity while others exhibit the opposite effect. He demonstrated that FABP4 is highly expressed in a subset of tumor associated macrophages (TAMs) with the phenotype of CD11b+F4/80+MHCII−Ly6C−CD11c−and showed that FABP4-positive TAM subset accumulates in the stroma of mammary tumors,which promote tumor growth through enhancing oncogenic IL-6 signaling. [16] In addition,he highlighted how FABP4 also promotes cancer risk through other mechanisms,including providing energy for rapid tumor growth through exergonic free fatty acid transport,enhancing new blood vessel formation,and inhibiting tumor suppressor genes. Collectively,his seminar studies uncovered that FABP4 strengthens interactions among tumor stromal macrophages,adipocytes,and tumor cells and connects obesity-associated adipokines to tumor-promoting signaling,thus representing a mechanism by which obesity increases the risk and development of breast cancer and potentially other types of obesity-associated cancers. [17]
Li's research demonstrated that FABP5 also known as epidermal FABP (E-FABP) due to its high expression in skin epidermis is expressed in certain immune cell subsets,including macrophages and T cells,regulating immune cell lipid metabolism and function in different chronic inflammatory diseases. While acknowledging that under non-obese homeostatic status,FABP5 functions to maintain energy balance and normal cell function,he studied the impact of FABP5 on innate immunity and uncovered that FABP5 expression in macrophages promotes type I IFN-βproduction,aiding antitumor cell recruitment and protection against tumor growth. [18] While researching the role of FABP5 in chronic inflammation and immune dysfunction triggered by excessive lipid intake,he induced an obese mouse model using different types of HFDs. Moreover,his studies have reported that various dietary fats exert distinct immunoregulatory effects. For instance,mice that are fed a lard-based high-fat diet showed increased dermatitis attributing to saturated lipids in the diet,which induce skin macrophages to produce the pro-inflammatory cytokine IL-1βin a manner dependent on FABP5. [19] In subsequent research,he investigated how mice consuming fish oil-based HFD exhibit enhanced FABP5/ROS/IL-36/TNFαsignaling in skin macrophages,leading to impaired hair follicles and hair loss. [20] Furthermore,while studying the role of FABP5 in regulating T cell metabolism and function. He demonstrated an obese mouse model induced by safflower-based HFD,linoleic acids (LA) rich in the safflower oil impairs T cell survival and anti-tumor function highlighting how FABP5 plays a critical role in mediating LA uptake and mitochondrial ROS production in T cells. The result of the research showed that obese mice developed bigger mammary tumor than low fat diet-fed lean mice. [21]
Besides dissecting the role of FABP5 in immunoregulation,Li's group also determined the role of FABP5 in skin pathology by focusing on its role in keratinocytes. His research brought to light the pivotal role played by FABP5 in averting chemical-induced skin tumor development. By orchestrating the IFN/p53/SOX2 pathway in keratinocytes,FABP5 emerges as a promising candidate for augmenting skin's innate immunity,hinting at future therapeutic implications. [22] In addition,his investigation unveiled a new role of FABP5 by mediating keratinocyte/immune cell crosstalk in skin tissue. His research shed light on the widespread use of depilatory creams for the removal of unwanted body hair investigating why the unknown reason for individuals with sensitive skin experiencing depilatory-induced skin burns and inflammation more than others. He looked into FABP5's role in inciting skin inflammation triggered by depilatory procedures,revealing its role as a key molecular trigger for hypersensitive skin reactions. [23]
Given the important role of FABPs in regulating cell lipid metabolism in obesity,chronic inflammation and cancer development,Li foundered the startup company BMImmune,trying to screen neutralizing antibodies and specific small molecular regulators in modification of FABP activities for potential clinical immunotherapy. His early studies demonstrated that the immunomodulatory agent β-glucan enhances anti-tumor therapeutic efficacy when combined with anti-tumor antibodies in different animal models. Furthermore,his findings have contributed to the FDA's approval for clinical phase II/III trials using yeast-derived β-glucan with anti-vascular epithelial growth factor mAb Avastin and anti-epidermal growth factor receptor mAb cetuximab for treatment of human lung cancer and metastatic colorectal cancer,respectively. [24] [25] [26]
Another aspect of prominence in Li's research is his focus on identifying an immunotherapeutic Cytotoxic T lymphocyte (CTL) epitope in hepatocellular carcinoma (HCC)-associated antigen HCA587 and its potential therapeutic strategies. His 2005 collaborative work identified a new CTL epitope,FLAKLNNTV,with potential for immunotherapies in HCC patients, [27] and assessed HCA587 as an immunotherapy target for HCC. Additionally,recombinant HCA587 protein was expressed and purified using the Bac-to-Bac system,facilitating future investigations into antibody generation and immune responses in HCC. [28] His research work also determined that there seems to be a correlation between the tumor differentiation of HCC and the expression of HCA587 protein,with a higher percentage of protein expression observed in poorly differentiated HCCs. [29]
Inflammation is part of the biological response of body tissues to harmful stimuli,such as pathogens,damaged cells,or irritants. It is a protective response involving immune cells,blood vessels,and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury,clear out damaged cells and tissues,and initiate tissue repair.
Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens,such as cancer cells,microbes,cellular debris,and foreign substances,which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis,which acts to defend the host against infection and injury.
Tumor necrosis factor is an adipokine and a cytokine. TNF is a member of the TNF superfamily,which consists of various transmembrane proteins with a homologous TNF domain.
Amphiregulin,also known as AREG,is a protein synthesized as a transmembrane glycoprotein with 252 aminoacids and it is encoded by the AREG gene. in humans.
The S100 proteins are a family of low molecular-weight proteins found in vertebrates characterized by two calcium-binding sites that have helix-loop-helix ("EF-hand-type") conformation. At least 21 different S100 proteins are known. They are encoded by a family of genes whose symbols use the S100 prefix,for example,S100A1,S100A2,S100A3. They are also considered as damage-associated molecular pattern molecules (DAMPs),and knockdown of aryl hydrocarbon receptor downregulates the expression of S100 proteins in THP-1 cells.
The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs,FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol,fatty acid,and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors,however,upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.
Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein,member of the toll-like receptor family,which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.
The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. Some family members are also believed to transport lipophilic molecules from outer cell membrane to certain intracellular receptors such as PPAR. The FABPs are intracellular carriers that “solubilize”the endocannabinoid anandamide (AEA),transporting AEA to the breakdown by FAAH,and compounds that bind to FABPs block AEA breakdown,raising its level. The cannabinoids are also discovered to bind human FABPs that function as intracellular carriers,as THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. Levels of fatty-acid-binding protein have been shown to decline with ageing in the mouse brain,possibly contributing to age-associated decline in synaptic activity.
S100 calcium-binding protein A7 (S100A7),also known as psoriasin,is a protein that in humans is encoded by the S100A7 gene.
Free fatty acid receptor 2(FFAR2),also termed G-protein coupled receptor 43 (GPR43),is a rhodopsin-like G-protein coupled receptor. It is coded by the FFAR2 gene. In humans,the FFAR2 gene is located on the long arm of chromosome 19 at position 13.12. Like other GPCRs,FFAR2s reside on the surface membrane of cells and when bond to one of their activating ligands regulate the function of their parent cells. FFAR2 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes three other receptors which,like FFAR2,are activated by certain fatty acids:FFAR1,FFAR3 (GPR41),and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids whereas FFAR1 and FFAR4 are activated by long-chain fatty acids.
Hydroxycarboxylic acid receptor 2 (HCA2),also known as GPR109A and niacin receptor 1 (NIACR1),is a protein which in humans is encoded (its formation is directed) by the HCAR2 gene and in rodents by the Hcar2 gene. The human HCAR2 gene is located on the long (i.e.,"q") arm of chromosome 12 at position 24.31 (notated as 12q24.31). Like the two other hydroxycarboxylic acid receptors,HCA1 and HCA3,HCA2 is a G protein-coupled receptor (GPCR) located on the surface membrane of cells. HCA2 binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid),butyric acid,and niacin (also known as nicotinic acid). β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA2. Under normal conditions,niacin's blood levels are too low to do so:it is given as a drug in high doses in order to reach levels that activate HCA2.
Free Fatty acid receptor 4 (FFAR4),also termed G-protein coupled receptor 120 (GPR120),is a protein that in humans is encoded by the FFAR4 gene. This gene is located on the long arm of chromosome 10 at position 23.33. G protein-coupled receptors reside on their parent cells' surface membranes,bind any one of the specific set of ligands that they recognize,and thereby are activated to trigger certain responses in their parent cells. FFAR4 is a rhodopsin-like GPR in the broad family of GPRs which in humans are encoded by more than 800 different genes. It is also a member of a small family of structurally and functionally related GPRs that include at least three other free fatty acid receptors (FFARs) viz., FFAR1,FFAR2,and FFAR3. These four FFARs bind and thereby are activated by certain fatty acids.
Allograft inflammatory factor 1 (AIF-1) also known as ionized calcium-binding adapter molecule 1 (IBA1) is a protein that in humans is encoded by the AIF1 gene.
C-type lectin domain family 10 member A (CLEC10A) also designated as CD301 is a protein that in humans is encoded by the CLEC10A gene. CLEC10A is part of the C-type lectin superfamily and binds to N-Acetylgalactosamine (GalNAc). It is mainly expressed on myeloid cells and also on oocytes and very early stages of embryogenesis. CLEC10A is used as a marker of the CD1c+ dendritic cell subgroup,also called cDC2. The actions of CLEC10A are diverse,depending on the ligand and environment.
Adipose tissue macrophages (ATMs) comprise tissue resident macrophages present in adipose tissue. Adipose tissue apart from adipocytes is composed of the stromal vascular fraction (SVF) of cells including preadipocytes,fibroblasts,vascular endothelial cells and variety of immune cells. The latter ones are composed of mast cells,eosinophils,B cells,T cells and macrophages. The number of macrophages within adipose tissue differs depending on the metabolic status. As discovered by Rudolph Leibel and Anthony Ferrante et al. in 2003 at Columbia University,the percentage of macrophages within adipose tissue ranges from 10% in lean mice and humans up to 50% in extremely obese,leptin deficient mice and almost 40% in obese humans. Increased number of adipose tissue macrophages correlates with increased adipose tissue production of proinflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity.
The S100 calcium-binding protein mS100a7a15 is the murine ortholog of human S100A7 (Psoriasin) and human S100A15 (Koebnerisin). mS100a7a15 is also known as S100a15,mS100a7 and mS100a7a and is encoded by the mS100a7a gene
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells,derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage,ILCs contribute to immunity via the secretion of signalling molecules,and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells,found in both lymphoid,and non- lymphoid tissues,and rarely in the blood. They are particularly abundant at mucosal surfaces,playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology,absence of rearranged antigen receptors found on T cells and B cells,and phenotypic markers usually present on myeloid or dendritic cells.
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage.
TNF alpha induced protein 8 like 2 (TNFAIP8L2),also known as TIPE2,is a protein that in humans is encoded by the TNFAIP8L2 gene. It is preferentially expressed in human myeloid cell types and serves as an immune checkpoint regulator of inflammation and metabolism.
Apoptosis inhibitor of macrophage (AIM) is a protein produced by macrophages that regulates immune responses and inflammation. It plays a crucial role in key intracellular processes like lipid metabolism and apoptosis.