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Luo Laboratory Research

Research Overview

One of the major players in innate immune system is neutrophil which is the most abundant cell type among circulating white blood cells and constitutes the first line of host defense against invading bacteria and other pathogens. In response to inflammatory stimuli, neutrophils migrate from the blood to infected tissues, where they protect their host by engulfing, killing, and digesting invading bacterial and fungal pathogens. Conversely, excessive neutrophil accumulation or hyper-responsiveness of neutrophils can be detrimental to the system. Hence, the production, recruitment, and response of neutrophils to inflammatory stimuli need to be well controlled. The long-term goal of our research is to elucidate the molecular mechanisms that control the production, trafficking, function, and fate of neutrophils during infection and inflammation. We are also interested in the potential role of neutrophils in regulating bone marrow hematopoiesis and tumorigenesis.

Currently, we are particularly interested in signaling pathways mediated by inositol phospholipid PtdIns(3,4,5)P3, inositol phosphates (e.g. InsP4 and InsP7), reactive oxygen species (ROS), and neutrophil serine proteinases (elastase, proteinase 3, and cathepsin G). We also identified gasdermin family proteins, particularly GSDMD and GSDME, as key cellular factors controlling neutrophil death and function. We utilize a wide variety of approaches ranging from basic molecular, cellular, and biochemical methods to automatic high-resolution imaging, scRNA-seq, high throughput chemical genetic screening, and animal inflammation models to dissect these pathways. The ultimate goal is to develop more efficient and effective therapies for treating various infectious and inflammatory diseases.

The full neutrophil heterogeneity and differentiation landscape remains incompletely characterized. Recently, we profiled >25,000 differentiating and mature mouse neutrophils using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function, and fate decision in their steady state and during bacterial infection. Eight neutrophil populations were defined by distinct molecular signatures. The three mature peripheral blood neutrophil subsets arise from distinct maturing bone marrow neutrophil subsets. Driven by both known and uncharacterized transcription factors, neutrophils gradually acquire microbicidal capability as they traverse the transcriptional landscape, representing an evolved mechanism for fine-tuned regulation of an effective but balanced neutrophil response. Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall heterogeneity. In summary, these data establish a reference model and general framework for studying neutrophil-related disease mechanisms, biomarkers, and therapeutic targets at single-cell resolution. We are presently investigating how neutrophil heterogeneity is regulated and contributes to host immune response in health and disease.

 

Research Background

Dr. Hongbo (Robert) Luo received his BS degree in Molecular Biology from Nankai University, China. Dr Luo's graduate research was carried out in the lab of Melissa Moore at Brandeis University. After finishing his postdoctoral training with Solomon Snyder at Johns Hopkins University, he was recruited to Harvard Medical School as an Assistant Professor of Pathology in 2004. He was promoted to Associate Professor in 2010 and Full Professor in 2018.

Publications

  1. Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity. Cell. 2024 Oct 31; 187(22):6165-6181.e22. View Abstract
  2. The effect of transient, constricted migration on neutrophil intracellular bacteria-killing capability. Immunity. 2024 08 13; 57(8):1713-1715. View Abstract
  3. The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis. Sci Immunol. 2024 Apr 12; 9(94):eadn1452. View Abstract
  4. ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D. Nature. 2024 Jun; 630(8016):437-446. View Abstract
  5. Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death. Nat Commun. 2024 Jan 09; 15(1):386. View Abstract
  6. HDAC6 deacetylates IDH1 to promote the homeostasis of hematopoietic stem and progenitor cells. EMBO Rep. 2023 10 09; 24(10):e56009. View Abstract
  7. NLRP3 is essential for neutrophil polarization and chemotaxis in response to leukotriene B4 gradient. Proc Natl Acad Sci U S A. 2023 08 29; 120(35):e2303814120. View Abstract
  8. Neutrophil-specific depletion of gasdermin D does not protect against murine sepsis. Blood. 2023 02 02; 141(5):550-554. View Abstract
  9. aDß2 as a novel target of experimental polymicrobial sepsis. Front Immunol. 2022; 13:1059996. View Abstract
  10. Identification of the Transgene Integration Site and Host Genome Changes in MRP8-Cre/ires-EGFP Transgenic Mice by Targeted Locus Amplification. Front Immunol. 2022; 13:875991. View Abstract
  11. Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages. Nat Commun. 2021 11 18; 12(1):6699. View Abstract
  12. Myeloid lineage contributes to pathological choroidal neovascularization formation via SOCS3. EBioMedicine. 2021 Nov; 73:103632. View Abstract
  13. Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion. Sci Transl Med. 2021 07 28; 13(604). View Abstract
  14. Rheb1-Deficient Neutrophils Promote Hematopoietic Stem/Progenitor Cell Proliferation via Mesenchymal Stem Cells. Front Cell Dev Biol. 2021; 9:650599. View Abstract
  15. Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown. Proc Natl Acad Sci U S A. 2021 03 02; 118(9). View Abstract
  16. Zinc Finger Protein SALL4 Functions through an AT-Rich Motif to Regulate Gene Expression. Cell Rep. 2021 01 05; 34(1):108574. View Abstract
  17. Single-cell transcriptome profiling reveals neutrophil heterogeneity in homeostasis and infection. Nat Immunol. 2020 09; 21(9):1119-1133. View Abstract
  18. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol. 2020 07; 21(7):736-745. View Abstract
  19. Bacteria-Induced Acute Inflammation Does Not Reduce the Long-Term Reconstitution Capacity of Bone Marrow Hematopoietic Stem Cells. Front Immunol. 2020; 11:626. View Abstract
  20. Interleukin-1ß inhibits normal hematopoietic expansion and promotes acute myeloid leukemia progression via the bone marrow niche. Cytotherapy. 2020 03; 22(3):127-134. View Abstract
  21. Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus. J Clin Invest. 2020 01 02; 130(1):422-437. View Abstract
  22. The role of CXCR2 in acute inflammatory responses and its antagonists as anti-inflammatory therapeutics. Curr Opin Hematol. 2019 01; 26(1):28-33. View Abstract
  23. Glutaredoxin 1 up-regulates deglutathionylation of a4 integrin and thereby restricts neutrophil mobilization from bone marrow. J Biol Chem. 2019 02 22; 294(8):2616-2627. View Abstract
  24. Proteinase 3 Limits the Number of Hematopoietic Stem and Progenitor Cells in Murine Bone Marrow. Stem Cell Reports. 2018 11 13; 11(5):1092-1105. View Abstract
  25. Rheb1 loss leads to increased hematopoietic stem cell proliferation and myeloid-biased differentiation in vivo. Haematologica. 2019 02; 104(2):245-255. View Abstract
  26. Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence. PLoS Pathog. 2018 07; 14(7):e1007076. View Abstract
  27. GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever. J Exp Med. 2018 06 04; 215(6):1519-1529. View Abstract
  28. Role of Selenof as a Gatekeeper of Secreted Disulfide-Rich Glycoproteins. Cell Rep. 2018 05 01; 23(5):1387-1398. View Abstract
  29. Histone deacetylase 6 modulates macrophage infiltration during inflammation. Theranostics. 2018; 8(11):2927-2938. View Abstract
  30. Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia. Sci Transl Med. 2018 04 04; 10(435). View Abstract
  31. Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death. Cell Rep. 2018 03 13; 22(11):2924-2936. View Abstract
  32. Positive Regulation of Interleukin-1ß Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation. Cell Rep. 2017 07 05; 20(1):224-235. View Abstract
  33. Heterogeneity of neutrophil spontaneous death. Am J Hematol. 2017 08; 92(8):E156-E159. View Abstract
  34. Reactive Oxygen Species-Producing Myeloid Cells Act as a Bone Marrow Niche for Sterile Inflammation-Induced Reactive Granulopoiesis. J Immunol. 2017 04 01; 198(7):2854-2864. View Abstract
  35. G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling. J Exp Med. 2016 09 19; 213(10):1999-2018. View Abstract
  36. E1A-engineered human umbilical cord mesenchymal stem cells as carriers and amplifiers for adenovirus suppress hepatocarcinoma in mice. Oncotarget. 2016 Aug 09; 7(32):51815-51828. View Abstract
  37. Kras is Required for Adult Hematopoiesis. Stem Cells. 2016 07; 34(7):1859-71. View Abstract
  38. Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability. Proc Natl Acad Sci U S A. 2015 Jun 09; 112(23):7255-60. View Abstract
  39. NFAT1 promotes intratumoral neutrophil infiltration by regulating IL8 expression in breast cancer. Mol Oncol. 2015 Jun; 9(6):1140-54. View Abstract
  40. Molecular control of PtdIns(3,4,5)P3 signaling in neutrophils. EMBO Rep. 2015 Feb; 16(2):149-63. View Abstract
  41. Myeloid cell-derived reactive oxygen species externally regulate the proliferation of myeloid progenitors in emergency granulopoiesis. Immunity. 2015 Jan 20; 42(1):159-71. View Abstract
  42. De novo chemoattractants form supramolecular hydrogels for immunomodulating neutrophils in vivo. Bioconjug Chem. 2014 Dec 17; 25(12):2116-22. View Abstract
  43. Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation. J Clin Invest. 2014 Oct; 124(10):4445-58. View Abstract
  44. Microtubule dynamics regulates Akt signaling via dynactin p150. Cell Signal. 2014 Aug; 26(8):1707-16. View Abstract
  45. A dual regulator of neutrophil recruitment. Blood. 2014 Mar 27; 123(13):1983-5. View Abstract
  46. A novel small-molecule tumor necrosis factor a inhibitor attenuates inflammation in a hepatitis mouse model. J Biol Chem. 2014 May 02; 289(18):12457-66. View Abstract
  47. Proteinase 3 and Serpin B1: a novel pathway in the regulation of caspase-3 activation, neutrophil spontaneous apoptosis, and inflammation. Inflamm Cell Signal. 2014; 1(6). View Abstract
  48. Inhibitors of neutrophil recruitment identified using transgenic zebrafish to screen a natural product library. Dis Model Mech. 2014 Jan; 7(1):163-9. View Abstract
  49. Blockade of glioma proliferation through allosteric inhibition of JAK2. Sci Signal. 2013 Jul 09; 6(283):ra55. View Abstract
  50. Deficiency of lipid phosphatase SHIP enables long-term reconstitution of hematopoietic inductive bone marrow microenvironment. Dev Cell. 2013 May 28; 25(4):333-49. View Abstract
  51. Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate. Proc Natl Acad Sci U S A. 2013 May 07; 110(19):7726-31. View Abstract
  52. O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity. Pharmacology. 2013; 91(3-4):185-200. View Abstract
  53. Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex. Blood. 2013 Feb 21; 121(8):1413-21. View Abstract
  54. Reactive oxygen species-induced actin glutathionylation controls actin dynamics in neutrophils. Immunity. 2012 Dec 14; 37(6):1037-49. View Abstract
  55. Leukotriene B4-driven neutrophil recruitment to the skin is essential for allergic skin inflammation. Immunity. 2012 Oct 19; 37(4):747-58. View Abstract
  56. Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression. J Med Chem. 2012 Oct 11; 55(19):8524-37. View Abstract
  57. Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death. Proc Natl Acad Sci U S A. 2012 Jun 26; 109(26):10581-6. View Abstract
  58. The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke. Nat Neurosci. 2012 Mar 04; 15(4):565-73. View Abstract
  59. Exploiting effectors of Rac GTPase. Chem Biol. 2012 Feb 24; 19(2):169-71. View Abstract
  60. Phosphoinositide lipid phosphatase SHIP1 and PTEN coordinate to regulate cell migration and adhesion. Mol Biol Cell. 2012 Apr; 23(7):1219-30. View Abstract
  61. [Novel neuroprotective agents: a HIF activator and an Akt activator]. Rinsho Shinkeigaku. 2012; 52(11):911-2. View Abstract
  62. Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion. Exp Hematol. 2012 Apr; 40(4):307-17.e3. View Abstract
  63. PTEN negatively regulates engulfment of apoptotic cells by modulating activation of Rac GTPase. J Immunol. 2011 Dec 01; 187(11):5783-94. View Abstract
  64. Identification of a molecular activator for insulin receptor with potent anti-diabetic effects. J Biol Chem. 2011 Oct 28; 286(43):37379-88. View Abstract
  65. Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling. Nat Immunol. 2011 Jun 19; 12(8):752-60. View Abstract
  66. Phosphoinositide 3-kinase enhancer regulates neuronal dendritogenesis and survival in neocortex. J Neurosci. 2011 Jun 01; 31(22):8083-92. View Abstract
  67. Guanine nucleotide exchange factor Vav1 regulates perivascular homing and bone marrow retention of hematopoietic stem and progenitor cells. Proc Natl Acad Sci U S A. 2011 Jun 07; 108(23):9607-12. View Abstract
  68. Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model. Blood. 2011 Jun 16; 117(24):6702-13. View Abstract
  69. Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination. Proc Natl Acad Sci U S A. 2011 Apr 19; 108(16):6486-91. View Abstract
  70. A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect. J Med Chem. 2010 Dec 09; 53(23):8274-86. View Abstract
  71. Reactive oxygen species as signaling molecules in neutrophil chemotaxis. Commun Integr Biol. 2010 May; 3(3):278-81. View Abstract
  72. Natural product Celastrol destabilizes tubulin heterodimer and facilitates mitotic cell death triggered by microtubule-targeting anti-cancer drugs. PLoS One. 2010 Apr 23; 5(4):e10318. View Abstract
  73. Integrin-independent role of CalDAG-GEFI in neutrophil chemotaxis. J Leukoc Biol. 2010 Aug; 88(2):313-9. View Abstract
  74. Fas-activated serine/threonine phosphoprotein promotes immune-mediated pulmonary inflammation. J Immunol. 2010 May 01; 184(9):5325-32. View Abstract
  75. Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis. Proc Natl Acad Sci U S A. 2010 Feb 23; 107(8):3546-51. View Abstract
  76. Neutrophil spontaneous death is mediated by down-regulation of autocrine signaling through GPCR, PI3Kgamma, ROS, and actin. Proc Natl Acad Sci U S A. 2010 Feb 16; 107(7):2950-5. View Abstract
  77. Deficiency of phosphoinositide 3-kinase enhancer protects mice from diet-induced obesity and insulin resistance. Diabetes. 2010 Apr; 59(4):883-93. View Abstract
  78. Focal adhesion kinase regulates pathogen-killing capability and life span of neutrophils via mediating both adhesion-dependent and -independent cellular signals. J Immunol. 2009 Jul 15; 183(2):1032-43. View Abstract
  79. Myeloid-specific deletion of tumor suppressor PTEN augments neutrophil transendothelial migration during inflammation. J Immunol. 2009 Jun 01; 182(11):7190-200. View Abstract
  80. Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. PLoS One. 2009; 4(5):e5577. View Abstract
  81. Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia. Blood. 2009 May 14; 113(20):4930-41. View Abstract
  82. Regulation of innate immunity by inositol 1,3,4,5-tetrakisphosphate. Cell Cycle. 2008 Sep 15; 7(18):2803-8. View Abstract
  83. Cancer cell-derived clusterin modulates the phosphatidylinositol 3'-kinase-Akt pathway through attenuation of insulin-like growth factor 1 during serum deprivation. Mol Cell Biol. 2008 Jul; 28(13):4285-99. View Abstract
  84. Constitutive neutrophil apoptosis: mechanisms and regulation. Am J Hematol. 2008 Apr; 83(4):288-95. View Abstract
  85. Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase. Mol Cell. 2008 Mar 28; 29(6):665-78. View Abstract
  86. Inositol trisphosphate 3-kinase B (InsP3KB) as a physiological modulator of myelopoiesis. Proc Natl Acad Sci U S A. 2008 Mar 25; 105(12):4739-44. View Abstract
  87. SOCS3 protein developmentally regulates the chemokine receptor CXCR4-FAK signaling pathway during B lymphopoiesis. Immunity. 2007 Nov; 27(5):811-23. View Abstract
  88. Inositol 1,3,4,5-tetrakisphosphate negatively regulates phosphatidylinositol-3,4,5- trisphosphate signaling in neutrophils. Immunity. 2007 Sep; 27(3):453-67. View Abstract
  89. Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells. Proc Natl Acad Sci U S A. 2007 Aug 28; 104(35):13978-83. View Abstract
  90. RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acid-induced cell growth arrest in human acute promyelocytic NB4 cells. Blood. 2007 Jul 15; 110(2):640-50. View Abstract
  91. The cationic amino acid transporters CAT1 and CAT3 mediate NMDA receptor activation-dependent changes in elaboration of neuronal processes via the mammalian target of rapamycin mTOR pathway. J Neurosci. 2007 Jan 17; 27(3):449-58. View Abstract
  92. Tumor suppressor PTEN is a physiologic suppressor of chemoattractant-mediated neutrophil functions. Blood. 2007 May 01; 109(9):4028-37. View Abstract
  93. Deactivation of phosphatidylinositol 3,4,5-trisphosphate/Akt signaling mediates neutrophil spontaneous death. Proc Natl Acad Sci U S A. 2006 Oct 03; 103(40):14836-41. View Abstract
  94. S-nitrosylation of N-ethylmaleimide sensitive factor mediates surface expression of AMPA receptors. Neuron. 2005 May 19; 46(4):533-40. View Abstract
  95. Inositol hexakisphosphate kinase-2, a physiologic mediator of cell death. J Biol Chem. 2005 Jan 14; 280(2):1634-40. View Abstract
  96. Novel mechanism of PTEN regulation by its phosphatidylinositol 4,5-bisphosphate binding motif is critical for chemotaxis. J Biol Chem. 2004 Apr 16; 279(16):16606-13. View Abstract
  97. Akt as a mediator of cell death. Proc Natl Acad Sci U S A. 2003 Sep 30; 100(20):11712-7. View Abstract
  98. Inositol pyrophosphates mediate chemotaxis in Dictyostelium via pleckstrin homology domain-PtdIns(3,4,5)P3 interactions. Cell. 2003 Sep 05; 114(5):559-72. View Abstract
  99. Inositol pyrophosphates are required for DNA hyperrecombination in protein kinase c1 mutant yeast. Biochemistry. 2002 Feb 26; 41(8):2509-15. View Abstract
  100. Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE. Nature. 2002 Jan 31; 415(6871):541-4. View Abstract

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