Edward R. Sherwood, Ph.D., M.D.

Professor

edward.r.sherwood@vanderbilt.edu
Faculty Appointments
Professor of Anesthesiology Cornelius Vanderbilt Chair in AnesthesiologyProfessor of Pathology, Microbiology and Immunology
Education
M.D., Medicine, University of Chicago Pritzker School of Medicine, Chicago, IllinoisPh.D., Physiology, Tulane University, New Orleans, LouisianaB.S., Southwestern University , Georgetown, Texas
Office Address
Vanderbilt University Medical Center
1161 Medical Center Drive
Nashville, TN 37232
Research Description
Sherwood Research Program
R01 AI151210
Macrophage mitochodrial reprogramming and innate immune memory

Hospital-acquired infections are a major threat to public health, impacting 2 million patients and causing at least 90,000 deaths annually. Sepsis is a common complication in patients with hospital-acquired infections and the leading cause of death in non-cardiac intensive care units (ICU). Attempts at treating hospital-acquired infections and sepsis have proven exceedingly difficult and patients that survive sepsis suffer long-term physical and cognitive disabilities and a high 1-year mortality rate. Therefore, new strategies are needed to decrease the burden of hospital-acquired infections and sepsis. Immunotherapy aimed at inducing innate immune memory provides a way of achieving that goal. Recent studies show that innate immune cells can retain memory of prior pathogen exposure and are primed to elicit a robust, broad-spectrum antimicrobial response to subsequent infection. Treatment with TLR4 ligands, such as monophosphoryl lipid A (MPLA), confers innate immune memory and resistance to a broad array of clinically important pathogens that persists for more than 2 weeks. We propose that the appropriate application of TLR4 ligand-based immunotherapy to induce innate immune memory has significant potential to reduce the burden of hospital-acquired infections and sepsis. Macrophages are the foundation for development of innate immune memory. Recent evidence indicates that remodeling of macrophage metabolism is central to the
induction of innate immune memory. Priming with TLR4 ligands induces a macrophage metabolic phenotype characterized by increased glycolysis, oxidative metabolism and mitochondrial biogenesis with increased citric acid cycle flux and associated increases in immunoresponsive gene 1 (Irg1) expression and itaconate production. We hypothesize that macrophage metabolic remodeling and the increased production of Irg1 and itaconate are essential to generating innate immune memory. To define the underlying biology,
we will: (1). Determine how Irg1 and itaconate drive TLR4 agonist-induced innate immune memory in macrophages; (2). Define the importance of Irg1, itaconate and Nrf2 as regulators of the host response to infection with common hospital-acquired pathogens after TLR4 agonist treatment in vivo.; (3). Define the intracellular signaling pathways driving mitochondrial biogenesis, Irg1 expression and itaconate production in TLR4 agonist-primed macrophages; (4). Determine the ability of diverse microbial ligands to induce macrophage mitochondrial biogenesis, reprogram mitochondrial metabolism and function and induce innate immune memory. We will test the hypothesis that, like TLR4 agonists, microbial ligands such as peptidoglycan, CpG ODN and ß-glucan, have the ability to reprogram macrophage metabolism and induce a memory phenotype characterized by mitochondrial biogenesis, increased citric acid cycle flux, increased Irg1 expression and itaconate production with associated enhancement of antimicrobial functions.

R01 GM119197
Training Innate Immunity: A new approach to the treatment of Sepsis

This revised competitive renewal application is submitted under the NIH multiple PI initiative
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-11-118.html). Drs. Ed Sherwood and David Williams will serve as the PIs. The multiple PI strategy is advantageous because it enables a “team science” approach that will draw equally on the expertise and experience of both of the PIs, their research groups and their respective institutions. The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis syndrome, septic shock and/or multiple organ dysfunction syndrome. In the United States ~951,000 patients/year develop sepsis with approximately half of these patients in the ICU and an overall mortality rate is 28.6%. Those patients that survive the initial septic event may ultimately succumb to widespread organ dysfunction that can be either acute, due to hyper-inflammatory responses, or more prolonged due to immune dysfunction. It is well accepted that sepsis causes suppression of the immune system and that sepsis-induced immunoparalysis predisposes the critically ill patient to secondary infections. Attempts at developing effective therapies to prevent or treat sepsis and its associated immunosuppression have proven to be exceedingly difficult. In fact, no drugs are currently approved by the FDA for the management of sepsis. Recent data have provided compelling evidence that the innate immune system can be “trained” to respond more rapidly and effectively to pathogens. In this revised application, we propose the novel concept that it may be possible to “train” the compromised immune system, such that an effective response can be mounted to existing and/or subsequent infections. We hypothesize that “innate immune training will reprogram the metabolic, transcriptomic, epigenomic and functional phenotype of monocytes and macrophages from patients with sepsis and confer augmented resistance to infection”. To critically evaluate this hypothesis, we propose the following specific aims. Aim 1. Define the functional role of ß-glucan-induced metabolic reprogramming for inducing and sustaining trained immunity in human monocytes and macrophages. In this aim, we will explore the cellular and molecular mechanisms that are essential for induction of the trained phenotype. Specifically, we will investigate the metabolic phenotype of trained human monocyte/macrophages and determine the functional importance of metabolic reprogramming for inducing and sustaining the trained phenotype in leukocytes. Aim 2. Elucidate the mechanisms of innate immune training in human adults as a function of age. In this aim, we will examine the impact of immune training on leukocytes from aginghumans. In ex vivo experiments, we will examine cytokine secretion, metabolic reprogramming, gene expression, the epigenome, mitochondrial function and the anti-microbial functions of human monocytes and macrophages in response to immune training. Aim 3. Examine the effect of immune training in leukocytes isolated from sepsis patients. In this aim, we will employ monocytes or monocyte derived macrophages from sepsis patients. We will examine the effect of immune training on metabolic reprogramming, gene expression, the epigenome, mitochondrial activity and functionality of human monocytes and macrophages from septic patients. Successful completion of this research will provide a wealth of new and novel information on the mechanisms driving trained immunity in the presence and absence of sepsis. Of greater significance, this research will investigate innate immune training as a strategy for preventing and/or ameliorating sepsis and septic sequelae in the critically ill patient.
Research Keywords
immunology, metabolism, host-pathogen interaction,
Publications
Hernandez A, Patil NK, Brewer M, Delgado R, Himmel L, Lopez LN, Bohannon JK, Owen AM, Sherwood ER, de Caestecker MP. Pretreatment with a novel Toll-like receptor 4 agonist attenuates renal ischemia-reperfusion injury. Am J Physiol Renal Physiol [print-electronic]. 2023 May 5/1/2023; 324(5): F472-F482-F482. PMID: 36995924, PMCID: PMC10151043, DOI: 10.1152/ajprenal.00248.2022, ISSN: 1522-1466.

Hernandez A, Zhou J, Bohannon JK, McBride MA, Gibson-Corley KN, Patil NK, Owen AM, Burelbach KR, Sherwood ER. INTRAPULMONARY TREATMENT WITH A NOVEL TLR4 AGONIST CONFERS PROTECTION AGAINST KLEBSIELLA PNEUMONIA. Shock [print-electronic]. 2022 Oct 10/1/2022; 58(4): 295-303. PMID: 36018281, PMCID: PMC9647733, PII: 00024382-202210000-00007, DOI: 10.1097/SHK.0000000000001977, ISSN: 1540-0514.

Sherwood ER, Burelbach KR, McBride MA, Stothers CL, Owen AM, Hernandez A, Patil NK, Williams DL, Bohannon JK. Innate Immune Memory and the Host Response to Infection. J Immunol. 2022 Feb 2/15/2022; 208(4): 785-92. PMID: 35115374, PMCID: PMC8982914, PII: jimmunol.2101058, DOI: 10.4049/jimmunol.2101058, ISSN: 1550-6606.

Owen AM, Luan L, Burelbach KR, McBride MA, Stothers CL, Boykin OA, Sivanesam K, Schaedel JF, Patil TK, Wang J, Hernandez A, Patil NK, Sherwood ER, Bohannon JK. MyD88-dependent signaling drives toll-like receptor-induced trained immunity in macrophages. Front Immunol. 2022; 13: 1044662. PMID: 36439136, PMCID: PMC9692127, DOI: 10.3389/fimmu.2022.1044662, ISSN: 1664-3224.

Gill PS, Ozment TR, Lewis NH, Sherwood ER, Williams DL. Trained Immunity Enhances Human Monocyte Function in Aging and Sepsis. Front Immunol. 2022; 13: 872652. PMID: 35693816, PMCID: PMC9174537, DOI: 10.3389/fimmu.2022.872652, ISSN: 1664-3224.

Stothers CL, Burelbach KR, Owen AM, Patil NK, McBride MA, Bohannon JK, Luan L, Hernandez A, Patil TK, Williams DL, Sherwood ER. ß-Glucan Induces Distinct and Protective Innate Immune Memory in Differentiated Macrophages. J Immunol [print-electronic]. 2021 Dec 12/1/2021; 207(11): 2785-98. PMID: 34740960, PMCID: PMC8612974, PII: jimmunol.2100107, DOI: 10.4049/jimmunol.2100107, ISSN: 1550-6606.

Sherwood ER, Williams DL. Reversal of sepsis-induced T cell dysfunction: OX-40 to the rescue? [editorial]. J Leukoc Biol [print-electronic]. 2021 Apr; 109(4): 689-91. PMID: 32991749, PMCID: PMC7987777, DOI: 10.1002/JLB.3CE0720-468, ISSN: 1938-3673.

Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, van Crevel R, Curtis N, DiNardo AR, Dominguez-Andres J, Duivenvoorden R, Fanucchi S, Fayad Z, Fuchs E, Hamon M, Jeffrey KL, Khan N, Joosten LAB, Kaufmann E, Latz E, Matarese G, van der Meer JWM, Mhlanga M, Moorlag SJCFM, Mulder WJM, Naik S, Novakovic B, O'Neill L, Ochando J, Ozato K, Riksen NP, Sauerwein R, Sherwood ER, Schlitzer A, Schultze JL, Sieweke MH, Benn CS, Stunnenberg H, Sun J, van de Veerdonk FL, Weis S, Williams DL, Xavier R, Netea MG. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol. 2021 Jan; 22(1): 2-6. PMID: 33293712, PMCID: PMC8020292, PII: 10.1038/s41590-020-00845-6, DOI: 10.1038/s41590-020-00845-6, ISSN: 1529-2916.

Watts BA, Tamayo E, Sherwood ER, Good DW. Monophosphoryl lipid A pretreatment suppresses sepsis- and LPS-induced proinflammatory cytokine production in the medullary thick ascending limb. Am J Physiol Renal Physiol [print-electronic]. 2020 Jul 7/1/2020; 319(1): F8-F18-F18. PMID: 32421349, PMCID: PMC7468828, DOI: 10.1152/ajprenal.00178.2020, ISSN: 1522-1466.

Fukuda S, Ihara K, Bohannon JK, Hernandez A, Patil NK, Luan L, Stothers C, Stark R, Prough DS, Herndon DN, Sherwood ER, Enkhbaatar P. Monophosphoryl Lipid a Attenuates Multiorgan Dysfunction During Post-Burn Pseudomonas Aeruginosa Pneumonia in Sheep. Shock. 2020 Mar; 53(3): 307-16. PMID: 31045990, PMCID: PMC6937402, PII: 00024382-202003000-00008, DOI: 10.1097/SHK.0000000000001364, ISSN: 1540-0514.

McBride MA, Patil TK, Bohannon JK, Hernandez A, Sherwood ER, Patil NK. Immune Checkpoints: Novel Therapeutic Targets to Attenuate Sepsis-Induced Immunosuppression. Front Immunol. 2020; 11: 624272. PMID: 33613563, PMCID: PMC7886986, DOI: 10.3389/fimmu.2020.624272, ISSN: 1664-3224.

McBride MA, Owen AM, Stothers CL, Hernandez A, Luan L, Burelbach KR, Patil TK, Bohannon JK, Sherwood ER, Patil NK. The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma. Front Immunol. 2020; 11: 1043. PMID: 32547553, PMCID: PMC7273750, DOI: 10.3389/fimmu.2020.01043, ISSN: 1664-3224.

Hernandez A, Patil NK, Stothers CL, Luan L, McBride MA, Owen AM, Burelbach KR, Williams DL, Sherwood ER, Bohannon JK. Immunobiology and application of toll-like receptor 4 agonists to augment host resistance to infection. Pharmacol Res [print-electronic]. 2019 Dec; 150: 104502. PMID: 31689522, PMCID: PMC6884699, PII: S1043-6618(19)32006-7, DOI: 10.1016/j.phrs.2019.104502, ISSN: 1096-1186.

Hernandez A, Luan L, Stothers CL, Patil NK, Fults JB, Fensterheim BA, Guo Y, Wang J, Sherwood ER, Bohannon JK. Phosphorylated Hexa-Acyl Disaccharides Augment Host Resistance Against Common Nosocomial Pathogens. Crit Care Med. 2019 Nov; 47(11): e930-e938-e938. PMID: 31567352, PMCID: PMC6791756, DOI: 10.1097/CCM.0000000000003967, ISSN: 1530-0293.

Watts BA, Tamayo E, Sherwood ER, Good DW. Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through induction of Tollip and negative regulation of IRAK-1. Am J Physiol Renal Physiol [print-electronic]. 2019 Sep 9/1/2019; 317(3): F705-F719-F719. PMID: 31241993, PMCID: PMC6766623, DOI: 10.1152/ajprenal.00170.2019, ISSN: 1522-1466.

Williams DL, Li C, Sherwood ER. Loss of monocyte metabolic plasticity in endotoxin tolerance: A model for understanding sepsis-induced immune paralysis? [editorial]. J Leukoc Biol [print-electronic]. 2019 Jul; 106(1): 7-9. PMID: 31087702, PMCID: PMC6597287, DOI: 10.1002/JLB.4CE0319-100R, ISSN: 1938-3673.

Patil NK, Bohannon JK, Hernandez A, Patil TK, Sherwood ER. Regulation of leukocyte function by citric acid cycle intermediates. J Leukoc Biol [print-electronic]. 2019 Jul; 106(1): 105-17. PMID: 30791134, PMCID: PMC6597293, DOI: 10.1002/JLB.3MIR1118-415R, ISSN: 1938-3673.

Patil NK, Bohannon JK, Sherwood ER. Metabolism drives monocytes during inflammation: What we do and do not know [editorial]. J Leukoc Biol [print-electronic]. 2019 Feb; 105(2): 211-3. PMID: 30618209, DOI: 10.1002/JLB.3CE1118-448R, ISSN: 1938-3673.

Watts BA, George T, Sherwood ER, Good DW. Monophosphoryl lipid A prevents impairment of medullary thick ascending limb [Formula: see text] absorption and improves plasma [Formula: see text] concentration in septic mice. Am J Physiol Renal Physiol [print-electronic]. 2018 Sep 9/1/2018; 315(3): F711-F725-F725. PMID: 29741098, PMCID: PMC6172583, DOI: 10.1152/ajprenal.00033.2018, ISSN: 1522-1466.

Fensterheim BA, Young JD, Luan L, Kleinbard RR, Stothers CL, Patil NK, McAtee-Pereira AG, Guo Y, Trenary I, Hernandez A, Fults JB, Williams DL, Sherwood ER, Bohannon JK. The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism. J Immunol [print-electronic]. 2018 Jun 6/1/2018; 200(11): 3777-89. PMID: 29686054, PMCID: PMC5964009, PII: jimmunol.1800085, DOI: 10.4049/jimmunol.1800085, ISSN: 1550-6606.

Francois B, Jeannet R, Daix T, Walton AH, Shotwell MS, Unsinger J, Monneret G, Rimmelé T, Blood T, Morre M, Gregoire A, Mayo GA, Blood J, Durum SK, Sherwood ER, Hotchkiss RS. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 2018 Mar 3/8/2018; 3(5): PMID: 29515037, PMCID: PMC5922293, PII: 98960, DOI: 10.1172/jci.insight.98960, ISSN: 2379-3708.

Guo Y, Patil NK, Luan L, Bohannon JK, Sherwood ER. The biology of natural killer cells during sepsis. Immunology [print-electronic]. 2018 Feb; 153(2): 190-202. PMID: 29064085, PMCID: PMC5765373, DOI: 10.1111/imm.12854, ISSN: 1365-2567.

Patil NK, Luan L, Bohannon JK, Hernandez A, Guo Y, Sherwood ER. Frontline Science: Anti-PD-L1 protects against infection with common bacterial pathogens after burn injury. J Leukoc Biol [print-electronic]. 2018 Jan; 103(1): 23-33. PMID: 29345058, PMCID: PMC9680647, DOI: 10.1002/JLB.5HI0917-360R, ISSN: 1938-3673.

Guo Y, Luan L, Patil NK, Sherwood ER. Immunobiology of the IL-15/IL-15Ra complex as an antitumor and antiviral agent. Cytokine Growth Factor Rev [print-electronic]. 2017 Dec; 38: 10-21. PMID: 28888485, PMCID: PMC5705392, PII: S1359-6101(17)30143-0, DOI: 10.1016/j.cytogfr.2017.08.002, ISSN: 1879-0305.

Fensterheim BA, Guo Y, Sherwood ER, Bohannon JK. The Cytokine Response to Lipopolysaccharide Does Not Predict the Host Response to Infection. J Immunol [print-electronic]. 2017 Apr 4/15/2017; 198(8): 3264-73. PMID: 28275139, PMCID: PMC5380530, PII: jimmunol.1602106, DOI: 10.4049/jimmunol.1602106, ISSN: 1550-6606.

Guo Y, Luan L, Patil NK, Wang J, Bohannon JK, Rabacal W, Fensterheim BA, Hernandez A, Sherwood ER. IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function. J Immunol [print-electronic]. 2017 Feb 2/1/2017; 198(3): 1320-33. PMID: 28031340, PMCID: PMC5263185, PII: jimmunol.1601486, DOI: 10.4049/jimmunol.1601486, ISSN: 1550-6606.

Hernandez A, Bohannon JK, Luan L, Fensterheim BA, Guo Y, Patil NK, McAdams C, Wang J, Sherwood ER. The role of MyD88- and TRIF-dependent signaling in monophosphoryl lipid A-induced expansion and recruitment of innate immunocytes. J Leukoc Biol [print-electronic]. 2016 Dec; 100(6): 1311-22. PMID: 27354411, PMCID: PMC5109999, PII: jlb.1A0216-072R, DOI: 10.1189/jlb.1A0216-072R, ISSN: 1938-3673.

Patil NK, Bohannon JK, Sherwood ER. Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression. Pharmacol Res [print-electronic]. 2016 Sep; 111: 688-702. PMID: 27468649, PMCID: PMC5026606, PII: S1043-6618(16)30685-5, DOI: 10.1016/j.phrs.2016.07.019, ISSN: 1096-1186.

Bohannon JK, Luan L, Hernandez A, Afzal A, Guo Y, Patil NK, Fensterheim B, Sherwood ER. Role of G-CSF in monophosphoryl lipid A-mediated augmentation of neutrophil functions after burn injury. J Leukoc Biol [print-electronic]. 2016 Apr; 99(4): 629-40. PMID: 26538529, PMCID: PMC4787290, PII: jlb.4A0815-362R, DOI: 10.1189/jlb.4A0815-362R, ISSN: 1938-3673.

Patil NK, Luan L, Bohannon JK, Guo Y, Hernandez A, Fensterheim B, Sherwood ER. IL-15 Superagonist Expands mCD8+ T, NK and NKT Cells after Burn Injury but Fails to Improve Outcome during Burn Wound Infection. PLoS One. 2016; 11(2): e0148452. PMID: 26859674, PMCID: PMC4747596, PII: PONE-D-15-47311, DOI: 10.1371/journal.pone.0148452, ISSN: 1932-6203.

Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, Sherwood ER. IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-¿. J Immunol [print-electronic]. 2015 Sep 9/1/2015; 195(5): 2353-64. PMID: 26216888, PMCID: PMC4543906, PII: jimmunol.1500300, DOI: 10.4049/jimmunol.1500300, ISSN: 1550-6606.

Hotchkiss RS, Sherwood ER. Immunology. Getting sepsis therapy right. Science. 2015 Mar 3/13/2015; 347(6227): 1201-2. PMID: 25766219, PMCID: PMC4398343, PII: 347/6227/1201, DOI: 10.1126/science.aaa8334, ISSN: 1095-9203.