Neutrophil-macrophage Interactions Govern Liver Immunity
Principal Investigator: Stephen Gregory
Abstract: The liver is the most important organ in the body for clearance of bacteria from the bloodstream, and prevention of septicemia and sepsis;the mechanisms are unclear. The majority of studies undertaken to date have focused on the function of resident tissue macrophages (Kupffer cells) that line the liver sinusoids, ndeed, it is often suggested that Kupffer cells ingest and kill the bulk of organisms taken up. Experiments reported first in our laboratory indicate that the actual mechanisms are far more complex. Rather, bacterial elimination is dependent upon the interaction of Kupffer cells and bactericidal neutrophils that immigrate rapidly in response to infection. The factors that effect neutrophil removal and resolution of the inflammatory response have not been addressed. Studies demonstrating neutrophils inside the Kupffer cells of infected mice suggest that neutrophil-Kupffer cell interaction may be crucial. It is hypothesize that this interaction is essential to inhibiting the uncontrolled discharge of toxic metabolic products by neutrophils, suppressing the pro-inflammatory activity of Kupffer cells, and preventing chronic liver inflammation. The SPECIFIC AIMS of this proposal are to: I. Define the role of Kupffer cells in regulating the inflammatory response of neutrophils to bacteria cleared by the liver;II. Determine the effect of neutrophils on cytokine production by Kupffer cells; and III.Contrast the factors that affect neutrophil-Kupffer cell interaction with the effects of those same factors on the interaction of neutrophils with mononuclear phagocytes that infiltrate the liver subsequent to infection. To avoid the artifacts that can plague other methodologies, experimentation will rely largely on quantitative real-time RT-analysisof the genes expressed by cells obtained by Laser Capture Microdissection. Experiments that examine the activities of purified Kupffer cells and neutrophil in vitro will corroborate these analyses. The results should drastically alter our current understanding of the roles of Kupffer cells, neutrophils, and the factors that regulate the inflammatory response to bacteria that invade the bloodstream. These, in turn, will afford a new understanding of the maladaptive responses to systemic infections, as well as to other pathological events that culminate in liver injury and organ failure. Consequently, they should provide valuable insights that enable the development of innovative strategies to improve treatment and prevent the devastating consequencesoften associated with septicemia and sepsis.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT
- Hepatic macrophages promote the neutrophil-dependent resolution of fibrosis in repairing cholestatic rat liversMark W Harty
Department of Surgery, The Warren Alpert Medical School of Brown University and Hasbro Children s Hospitals, Providence, RI 02903, USA
Surgery 143:667-78. 2008..We sought to determine the cellular and molecular requirements for repair after biliary decompression, focusing on the role of hepatic macrophages in regulating inflammation and matrix resolution...
- Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injuryCaroline C Duwaerts
Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
Liver Int 33:255-65. 2013....
- Cross-activating invariant NKT cells and kupffer cells suppress cholestatic liver injury in a mouse model of biliary obstructionCaroline C Duwaerts
Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America
PLoS ONE 8:e79702. 2013..Anti-LFA-1 pre-treatment reduced iNKT cell accumulation in these same animals. These data indicate that the LFA-1-dependent cross-activation of iNKT cells and Kupffer cells inhibits neutrophil accumulation and cholestatic liver injury. ..
- Laser capture microdissection and genetic analysis of carbon-labeled Kupffer cellsStephan Gehring
Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 55 Claverick Street, Providence, RI 02903, USA
World J Gastroenterol 15:1708-18. 2009..To develop a method of labeling and micro-dissecting mouse Kupffer cells within an extraordinarily short period of time using laser capture microdissection (LCM)...
- Neutrophils sequestered in the liver suppress the proinflammatory response of Kupffer cells to systemic bacterial infectionMartin Holub
Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown University Providence, RI 02903, USA
J Immunol 183:3309-16. 2009..These findings document the critical role of neutrophils in moderating the proinflammatory response of Kupffer cells to bacteria taken up by the liver...
- The role of hepatic invariant NKT cells in systemic/local inflammation and mortality during polymicrobial septic shockCaroline K Hu
Shock Trauma Research Laboratories, Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903, USA
J Immunol 182:2467-75. 2009..Together, these findings suggest that the activation of hepatic invariant NKT cells plays a critical role in regulating the innate immune/systemic inflammatory response and survival in a model of acute septic shock...
- NK cells suppress experimental cholestatic liver injury by an interleukin-6-mediated, Kupffer cell-dependent mechanismChao Wen Cheng
Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
J Hepatol 54:746-52. 2011..Here, we examined the response of NK cells to liver injury that occurs in a mouse model of biliary obstruction...
- Targeting the diverse immunological functions expressed by hepatic NKT cellsCaroline C Duwaerts
Rhode Island Hospital and The Warren Alpert Medical School at Brown University, Department of Medicine, Providence, RI 02903, USA
Expert Opin Ther Targets 15:973-88. 2011..Efforts are ongoing to develop α-galactosylceramide analogs that modulate iNKT cell activity and selectively promote IFN-γ or IL-4...
- Invariant natural killer T cells suppress the neutrophil inflammatory response in a mouse model of cholestatic liver damagePhilip Wintermeyer
Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Gastroenterology 136:1048-59. 2009..These invariant NKT (iNKT) cells have been implicated in cholestatic liver injury...
- Neutrophil depletion blocks early collagen degradation in repairing cholestatic rat liversMark W Harty
Department of Surgery, The Warren Alpert Medical School of Brown University, Hasbro Children s Hospital, Room 147, 593 Eddy Street, Providence, RI 02903, USA
Am J Pathol 176:1271-81. 2010....