Kodi S. Ravichandran

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Primary Appointment

Professor, Unaffiliated

Education

  • BVSc, Veterinary Medicine, Madras Veterinary College, Madras, India
  • PhD, Molecular and Cell Biology, University of Massachusetts, Amherst, MA
  • Postdoc, Immunology, Dana Farber Cancer Center

Research Disciplines

Biochemistry, Cancer Biology, Cardiovascular Biology, Cell and Developmental Biology, Immunology, Metabolism, Microbiology, Molecular Biology, Neuroimmunology, Neuroscience, Translational Science

Research Description

Mechanisms Regulating Engulfment of Apoptotic cells, and Signals Influencing Lymphocyte Development
Our laboratory currently focuses on two major areas.
1. Engulfment of apoptotic cells - the art of eating a good meal.
Everyday we turn over billions of cells as part of normal development and homeostasis. The recognition and phagocytic removal of such cells destined to die (mostly via 'apoptosis') is fundamentally important for our health. Failure to promptly and efficiently clear apoptotic cells can lead to chronic inflammation, autoimmunity and developmental defects. The apoptotic cell clearance is usually done by neighboring cells or by professional phagocytes such as macrophages and dendritic cells. In studying this process, we consider four broad issues related to 'eating an apoptotic meal'. The first issue is getting to the meal itself. This involves the release of so called 'find-me signals' from apoptotic cells that serve as attraction cues to recruit monocytes and macrophages near an apoptotic cell. We have recently identified a critical for the nucleotides ATP and UTP as find-me signals that are released in a regulated way very early on during apoptosis (Elliott et al. Nature, 2009; Checkeni et al., Nature, 2010; Poon et al., Nature 2014). The second issue is determining what is on the menu, and distinguishing the apoptotic cell from the neighboring healthy cells. This is achieved through expression of 'eat-me' signals on apoptotic cells and their recognition by receptors on phagocytes. Here, we focus on the ligands on the dying cell and receptors on phagocytes that are involved in the specific recognition of apoptotic cells. Our further work has identified a novel type of engulfment receptor (BAI1) that recognizes phosphatidylserine, a key eat-me signal exposed on apoptotic cells (Park et al. Nature 2007, Park et al. Current Biology, 2009; Hochreiter-Hufford et al., Nature 2013). The third issue is the act of eating the meal itself. Here, we focus on the specific intracellular signals that are initiated within the phagocyte when it comes in contact with apoptotic cells, and how this leads to cytoskeletal rearrangements of the phagocyte and internalization of the target. We have defined the signaling pathway downstream of BAI1 involving the proteins ELMO1, Dock180 and the small GTPase Rac. We have also defined a second signaling module that involves the membrane protein LRP1 and a small intracellular adapter protein GULP. (Gumienny et al. Cell , 2001, Brugnera et al. Nature Cell Biology, 2002; Lu et al. Nature Str Mol. Biol. , 2004; deBakker et al. Currently Biology, 2004; Lu et al. Current Biology , 2005; Ravichandran, Cell, 2003). We have also generated mice with knockout of specific engulfment genes and are currently characterizing them (Elliott et al., Nature, 2010). The fourth relates to 'after-the-meal' issues. Contrary to other types of phagocytosis (such as bacterial uptake), engulfment of apoptotic cells is 'immunologically silent'. We are interested in determining how apoptotic cells induce an anti-inflammatory state of the phagocyte, and how this relates to immune tolerance (Juncadella et al., Nature, 2013, Mauldin et al., Current Biology, 2013).). Another fun problem in considering one cell eating another is that the phagocyte essentially doubles its cellular contents (including protein, cholesterol, nucleotides etc.). We are addressing how the ingested cargo is processed within the phagocyte, and how the phagocyte manages homeostasis (Kinchen et al. Nature Cell Biology, 2008; Kiss et al. Current Biology, 2007; Ravichandran et al. Nature Rev Immunol. 2007; Kinchen et al, Nature 2010; Fond et al., J of Clinical Investigation, 2015), and how what controls an appetite of the phagocyte in ingesting multiple apoptotic cells (Park et al., Nature, 2011). Recently, we have also become very interested in how phagocytes communicate with each other in a tissue (Han et al., Nature, 2016) and how one can boost cell clearance in vivo (Lee et al., Immunity, 2016). The overall goal of these studies is to understand the signaling pathways and the consequences of engulfment at the molecular, cellular and whole organism levels. We use a combination of molecular biology, cell biology, biochemistry, coupled with C.elegans and mouse knockout studies, to gain insights on how specific proteins orchestrate the intracellular signaling during engulfment and lead to the immunologically silent clearance of apoptotic cells. These could have implications for future therapies aimed at limiting inflammation (Elliott et al., Journal of Cell Biol, 2010).
2. Intracellular signaling pathways regulating T and B lymphocyte function.
Our particular focus is on how adapter proteins (which do not have any obvious catalytic activity but mediate protein:protein or protein:lipid interactions) regulate B and T cell development and function. We are addressing how the adapter protein Shc regulates specific checkpoints during T cell development in the thymus, as well as B cell development in the bone marrow. We have generated mice carrying targeted shc1 locus that would allow tissue-specific knockout of Shc expression, and also inducible transgenic mice expressing dominant negative forms of Shc. By disrupting Shc function at different stages of development, we are examining the function of Shc during lymphocyte development and subsequent immune responses in the periphery (Ravichandran et al. Science, 1993; Zhang et al. Nature Immunology, 2002; Trampont et al. Molecular Cell Biology, 2006). We have also been focusing on the role of the chemokine receptor CXCR4 (also a coreceptor for HIV-1) in regulating specific developmental steps during thymic T cell development (Trampont et al. Nature Immunology, 2009).

Personal Statement

Mechanisms Regulating Engulfment of Apoptotic cells,
and Signals Influencing Lymphocyte Development

Our laboratory currently focuses on two major areas.
1. Engulfment of apoptotic cells - the art of eating a good meal.
Everyday we turn over billions of cells as part of normal development and homeostasis. The recognition and phagocytic removal of such cells destined to die (mostly via 'apoptosis') is fundamentally important for our health. Failure to promptly and efficiently clear apoptotic cells can lead to chronic inflammation, autoimmunity and developmental defects. The apoptotic cell clearance is usually done by neighboring cells or by professional phagocytes such as macrophages and dendritic cells.
In studying this process, we consider four broad issues related to 'eating an apoptotic meal'. The first issue is getting to the meal itself. This involves the release of so called 'find-me signals' from apoptotic cells that serve as attraction cues to recruit monocytes and macrophages near an apoptotic cell. We have recently identified a critical for the nucleotides ATP and UTP as find-me signals that are released in a regulated way very early on during apoptosis (Elliott et al. Nature, 2009; Checkeni et al., Nature, 2010 ).
The second issue is determining what is on the menu, and distinguishing the apoptotic cell from the neighboring healthy cells. This is achieved through expression of 'eat-me' signals on apoptotic cells and their recognition by receptors on phagocytes. Here, we focus on the ligands on the dying cell and receptors on phagocytes that are involved in the specific recognition of apoptotic cells. Our recent work has identified a novel type of engulfment receptor (BAI1) that recognizes phosphatidylserine, a key eat-me signal exposed on apoptotic cells (Park et al. Nature 2007, Park et al. Current Biology, 2009).
The third issue is the act of eating the meal itself. Here, we focus on the specific intracellular signals that are initiated within the phagocyte when it comes in contact with apoptotic cells, and how this leads to cytoskeletal rearrangements of the phagocyte and internalization of the target. We have defined the signaling pathway downstream of BAI1 involving the proteins ELMO1, Dock180 and the small GTPase Rac. We have also defined a second signaling module that involves the membrane protein LRP1 and a small intracellular adapter protein GULP. (Gumienny et al. Cell , 2001, Brugnera et al. Nature Cell Biology, 2002; Lu et al. Nature Str Mol. Biol. , 2004; deBakker et al. Currently Biology, 2004; Lu et al. Current Biology , 2005; Ravichandran, Cell, 2003). We have also generated mice with knockout of specific engulfment genes and are currently characterizing them (Elliott et al., Nature, 2010).
The fourth relates to 'after-the-meal' issues. Contrary to other types of phagocytosis (such as bacterial uptake), engulfment of apoptotic cells is 'immunologically silent'. We are interested in determining how apoptotic cells induce an anti-inflammatory state of the phagocyte, and how this relates to immune tolerance (Juncadella et al., Nature, 2013, Mauldin et al., Current Biology, 2013).). Another fun problem in considering one cell eating another is that the phagocyte essentially doubles its cellular contents (including protein, cholesterol, nucleotides etc.). We are addressing how the ingested cargo is processed within the phagocyte, and how the phagocyte manages homeostasis (Kinchen et al. Nature Cell Biology, 2008; Kiss et al. Current Biology, 2007; Ravichandran et al. Nature Rev Immunol. 2007; Kinchen et al, Nature 2010), and how what controls an appetite of the phagocyte in ingesting multiple apoptotic cells (Park et al., Nature, 2011).
The overall goal of these studies is to understand the signaling pathways and the consequences of engulfment at the molecular, cellular and whole organism levels. We use a combination of molecular biology, cell biology, biochemistry, coupled with C.elegans and mouse knockout studies, to gain insights on how specific proteins orchestrate the intracellular signaling during engulfment and lead to the immunologically silent clearance of apoptotic cells. These could have implications for future therapies aimed at limiting inflammation (Elliott et al., Journal of Cell Biol, 2010).
2. Intracellular signaling pathways regulating T and B lymphocyte function.
Our particular focus is on how adapter proteins (which do not have any obvious catalytic activity but mediate protein:protein or protein:lipid interactions) regulate B and T cell development and function. We are addressing how the adapter protein Shc regulates specific checkpoints during T cell development in the thymus, as well as B cell development in the bone marrow. We have generated mice carrying targeted shc1 locus that would allow tissue-specific knockout of Shc expression, and also inducible transgenic mice expressing dominant negative forms of Shc. By disrupting Shc function at different stages of development, we are examining the function of Shc during lymphocyte development and subsequent immune responses in the periphery (Ravichandran et al. Science, 1993; Zhang et al. Nature Immunology, 2002; Trampont et al. Molecular Cell Biology, 2006). We have also been focusing on the role of the chemokine receptor CXCR4 (also a coreceptor for HIV-1) in regulating specific developmental steps during thymic T cell development (Trampont et al. Nature Immunology, 2009).

Training

  • Basic Cardiovascular Research Training Grant
  • Cancer Research Training in Molecular Biology
  • Interdisciplinary Training Program in Immunology
  • Predoctoral Training in Neuroscience
  • Training in Cell and Molecular Biology
  • Training in the Pharmacological Sciences

Selected Publications

Medina CB, Mehrotra P, Arandjelovic S, Perry JSA, Guo Y, Morioka S, Barron B, Walk SF, Ghesquière B, Krupnick AS, Lorenz U, Ravichandran KS, Metabolites released from apoptotic cells act as tissue messengers., 2020; Nature. 580(7801) 130-135. PMID: 32238926

Rival CM, Xu W, Shankman LS, Morioka S, Arandjelovic S, Lee CS, Wheeler KM, Smith RP, Haney LB, Isakson BE, Purcell S, Lysiak JJ, Ravichandran KS, Phosphatidylserine on viable sperm and phagocytic machinery in oocytes regulate mammalian fertilization., 2019; Nature communications. 10(1) 4456. PMID: 31575859 | PMCID: PMC6773685

Perry JSA, Morioka S, Medina CB, Iker Etchegaray J, Barron B, Raymond MH, Lucas CD, Onengut-Gumuscu S, Delpire E, Ravichandran KS, Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway., 2019; Nature cell biology. 21(12) 1532-1543. PMID: 31792382

Morioka S, Maueröder C, Ravichandran KS, Living on the Edge: Efferocytosis at the Interface of Homeostasis and Pathology., 2019; Immunity. 50(5) 1149-1162. PMID: 31117011 | PMCID: PMC6721617

Arandjelovic S, Perry JSA, Lucas CD, Penberthy KK, Kim TH, Zhou M, Rosen DA, Chuang TY, Bettina AM, Shankman LS, Cohen AH, Gaultier A, Conrads TP, Kim M, Elliott MR, Ravichandran KS, A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis., 2019; Nature immunology. 20(2) 141-151. PMID: 30643265 | PMCID: PMC6402828

Morioka S, Perry JSA, Raymond MH, Medina CB, Zhu Y, Zhao L, Serbulea V, Onengut-Gumuscu S, Leitinger N, Kucenas S, Rathmell JC, Makowski L, Ravichandran KS, Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release., 2018; Nature. 563(7733) 714-718. PMID: 30464343 | PMCID: PMC6331005

Han CZ, Juncadella IJ, Kinchen JM, Buckley MW, Klibanov AL, Dryden K, Onengut-Gumuscu S, Erdbrügger U, Turner SD, Shim YM, Tung KS, Ravichandran KS, Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation., 2016; Nature. 539(7630) 570-574. PMID: 27820945 | PMCID: PMC5799085

Lee CS, Penberthy KK, Wheeler KM, Juncadella IJ, Vandenabeele P, Lysiak JJ, Ravichandran KS, Boosting Apoptotic Cell Clearance by Colonic Epithelial Cells Attenuates Inflammation In Vivo., 2016; Immunity. 44(4) 807-20. PMID: 27037190 | PMCID: PMC4838559

Fond AM, Lee CS, Schulman IG, Kiss RS, Ravichandran KS, Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1., 2015; The Journal of clinical investigation. 125(7) 2748-58. PMID: 26075824 | PMCID: PMC4563683

Poon IK, Chiu YH, Armstrong AJ, Kinchen JM, Juncadella IJ, Bayliss DA, Ravichandran KS, Unexpected link between an antibiotic, pannexin channels and apoptosis., 2014; Nature. 507(7492) 329-34. PMID: 24646995 | PMCID: PMC4078991

Hochreiter-Hufford AE, Lee CS, Kinchen JM, Sokolowski JD, Arandjelovic S, Call JA, Klibanov AL, Yan Z, Mandell JW, Ravichandran KS, Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion., 2013; Nature. 497(7448) 263-7. PMID: 23615608 | PMCID: PMC3773542

Juncadella IJ, Kadl A, Sharma AK, Shim YM, Hochreiter-Hufford A, Borish L, Ravichandran KS, Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation., 2012; Nature. () . PMID: 23235830 | PMCID: PMC3662023

Park D, Han CZ, Elliott MR, Kinchen JM, Trampont PC, Das S, Collins S, Lysiak JJ, Hoehn KL, Ravichandran KS, Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein., 2011; Nature. 477(7363) 220-4. PMID: 21857682 | PMCID: PMC3513690

Elliott MR, Zheng S, Park D, Woodson RI, Reardon MA, Juncadella IJ, Kinchen JM, Zhang J, Lysiak JJ, Ravichandran KS, Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo., 2010; Nature. 467(7313) 333-7. PMID: 20844538 | PMCID: PMC3773546

Kinchen JM, Ravichandran KS, Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells., 2010; Nature. 464(7289) 778-82. PMID: 20305638 | PMCID: PMC2901565

Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, Armstrong AJ, Penuela S, Laird DW, Salvesen GS, Isakson BE, Bayliss DA, Ravichandran KS, Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis., 2010; Nature. 467(7317) 863-7. PMID: 20944749 | PMCID: PMC3006164

Trampont PC, Tosello-Trampont AC, Shen Y, Duley AK, Sutherland AE, Bender TP, Littman DR, Ravichandran KS, CXCR4 acts as a costimulator during thymic beta-selection., 2009; Nature immunology. 11(2) 162-70. PMID: 20010845 | PMCID: PMC2808461

Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, Park D, Woodson RI, Ostankovich M, Sharma P, Lysiak JJ, Harden TK, Leitinger N, Ravichandran KS, Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance., 2009; Nature. 461(7261) 282-6. PMID: 19741708 | PMCID: PMC2851546

Kinchen JM, Doukoumetzidis K, Almendinger J, Stergiou L, Tosello-Trampont A, Sifri CD, Hengartner MO, Ravichandran KS, A pathway for phagosome maturation during engulfment of apoptotic cells., 2008; Nature cell biology. 10(5) 556-66. PMID: 18425118 | PMCID: PMC2851549

Stites EC, Trampont PC, Ma Z, Ravichandran KS, Network analysis of oncogenic Ras activation in cancer., 2007; Science (New York, N.Y.). 318(5849) 463-7. PMID: 17947584

Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW, Ravichandran KS, BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module., 2007; Nature. 450(7168) 430-4. PMID: 17960134

Lu M, Kinchen JM, Rossman KL, Grimsley C, deBakker C, Brugnera E, Tosello-Trampont AC, Haney LB, Klingele D, Sondek J, Hengartner MO, Ravichandran KS, PH domain of ELMO functions in trans to regulate Rac activation via Dock180., 2004; Nature structural & molecular biology. 11(8) 756-62. PMID: 15247908

Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS, Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex., 2002; Nature cell biology. 4(8) 574-82. PMID: 12134158

Zhang L, Camerini V, Bender TP, Ravichandran KS, A nonredundant role for the adapter protein Shc in thymic T cell development., 2002; Nature immunology. 3(8) 749-55. PMID: 12101399

Gumienny TL, Brugnera E, Tosello-Trampont AC, Kinchen JM, Haney LB, Nishiwaki K, Walk SF, Nemergut ME, Macara IG, Francis R, Schedl T, Qin Y, Van Aelst L, Hengartner MO, Ravichandran KS, CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration., 2001; Cell. 107(1) 27-41. PMID: 11595183