Debroski Herbert, PhD

What I Do

      In order to fulfill a life-long dream, I traveled to South Africa to perform post-doctoral research at Groote Schuur Hospital, (University of Cape Town) in the laboratory of Frank Brombacher Ph.D. It was here that we provided the first evidence that interleukin 4-driven alternatively activated macrophages were necessary to suppress microbial-driven intestinal inflammation and immunopathology caused by the human parasitic helminth Schistosoma mansoni (Herbert et al. 2004 Immunity).

      Upon returning to the United States, I joined the laboratory of Fred. D. Finkelman M.D. to continue my study of Type 2 dependent effector molecules in host immunity against parasitic worms. In the schistosomiasis model, we demonstrated that interleukin 10 and TGF-beta serve distinct immunoregulatory roles in controlling liver immunopathology (Herbert et al. 2008 Journal of Immunology). We demonstrated that Arginase I (a product of alternatively activated macrophages) counter-regulates TH1/TH17-associated inflammation directed against worm ova within the intestine (Herbert et al. 2010 Journal of Immunology). We also demonstrated that IL-4/IL-13 dependent effects on goblet cells (specialized epithelia) mediated the production of RELM-beta, which limited the ability of gastrointestinal nematode parasites to feed and reside within the host (Herbert et al. 2009 Journal of Experimental Medicine).

        As principal investigator, my laboratory has uncovered that the mucosal repair molecule, Trefoil factor 2 initiates Type 2 cytokine production within hookworm-damaged lung tissue (Wills-Karp et al. 2012 Journal of Experimental Medicine). In addition, we are investigating how TGF-beta specifically regulates myeloid cell function to promote the resolution of tissue injury (Rani et al. 2011,  Heitmann et al. 2012 ). Ongoing studies are designed to better understand the orchestration of Type 2 inflammation and tissue repair at mucosal surfaces.

Biography

RESEARCH PROGRAM

The Herbert lab is investigating how mucosal epithelia and macrophages function together to maintain and restore pulmonary function under steady-state and infectious conditions. Our main project centers upon Trefoil factor proteins, a largely enigmatic family of mucosal cytokines, in controlling immunity at the mucosal interface. One of our most recent findings is that TFF2 is expressed within various macrophage populations of humans and mice and promotes a wound healing/M2 phenotype. Our generation of a novel co-culture system called the macrophage-epithelial repair assay (MERA), which uses primary epithelia and tissue macrophages, has facilitated the discovery that TFF2 interfaces with the Wnt pathway to facilitate epithelial regeneration.
Our lab is also investigating how metabolic enzymes regulate host immunity against parasite infection. This is because gastrointestinal (GI) nematodes exert profound metabolic demands upon their hosts, but how this affects immune cell function is entirely unclear. The hypothesis driving this project is that metabolic enzyme dysregulation favors chronic GI nematode infection. We have generated mutant mice with either a cell-specific deletion or over-expression of the catalytic a subunit of adenosine monophosphate kinase (AMPK) a heterotrimeric enzyme complex of aß? subunits that restores cellular energy. Recent data show that deletion of AMPK in alveolar macrophages disrupts host immunity and tissue repair during infection with the parasitic hookworm Nippostrongylus brasiliensis. Hence, our laboratory is poised to gain unique insight(s) into the molecular mechanisms that govern the host-pathogen interface and mucosal immunity at barrier surfaces.

Publications

  1. Fontana MF, Baccarella A, Kellar D, Oniskey TK, Terinate P, Rosenberg SD, Huang EJ, Herbert DR, Kim CC. Myeloid expression of the AP-1 transcription factor JUNB modulates outcomes of type 1 and type 2 parasitic infections. Parasite Immunol. 2015 Sep; 37(9):470-8.
  2. Karo-Atar D, Bordowitz A, Wand O, Pasmanik-Chor M, Fernandez IE, Itan M, Frenkel R, Herbert DR, Finkelman FD, Eickelberg O, Munitz A. A protective role for IL-13 receptor a 1 in bleomycin-induced pulmonary injury and repair. Mucosal Immunol. 2016 Jan; 9(1):240-53.
  3. Fontana MF, Baccarella A, Pancholi N, Pufall MA, Herbert DR, Kim CC. JUNB is a key transcriptional modulator of macrophage activation. J Immunol. 2015 Jan 1; 194(1):177-86.
  4. Apiwattanakul N, Thomas PG, Kuhn RE, Herbert DR, McCullers JA. Helminth infections predispose mice to pneumococcal pneumonia but not to other pneumonic pathogens. Med Microbiol Immunol. 2014 Oct; 203(5):357-64.
  5. McBerry C, Dias A, Shryock N, Lampe K, Gutierrez FR, Boon L, De'Broski RH, Aliberti J. PD-1 modulates steady-state and infection-induced IL-10 production in vivo. Eur J Immunol. 2014 Feb; 44(2):469-79.
  6. Licona-Limón P, Henao-Mejia J, Temann AU, Gagliani N, Licona-Limón I, Ishigame H, Hao L, Herbert DR, Flavell RA. Th9 Cells Drive Host Immunity against Gastrointestinal Worm Infection. Immunity. 2013 Oct 17; 39(4):744-57.
  7. Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, Di Serio C, Bacchetta R, Andreani M, Brockmann L, Gregori S, Flavell RA, Roncarolo MG. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013 Jun; 19(6):739-46.
  8. You D, Marr N, Saravia J, Shrestha B, Lee GI, Turvey SE, Brombacher F, Herbert DR, Cormier SA. IL-4Ra on CD4+ T cells plays a pathogenic role in respiratory syncytial virus reinfection in mice infected initially as neonates. J Leukoc Biol. 2013 Jun; 93(6):933-42.
  9. Hung LY, Lewkowich IP, Dawson LA, Downey J, Yang Y, Smith DE, Herbert DR. IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms. Proc Natl Acad Sci U S A. 2013 Jan 2; 110(1):282-7.
  10. Heitmann L, Rani R, Dawson L, Perkins C, Yang Y, Downey J, Hölscher C, Herbert DR. TGF-ß-responsive myeloid cells suppress type 2 immunity and emphysematous pathology after hookworm infection. Am J Pathol. 2012 Sep; 181(3):897-906.
  11. McBerry C, Egan CE, Rani R, Yang Y, Wu D, Boespflug N, Boon L, Butcher B, Mirpuri J, Hogan SP, Denkers EY, Aliberti J, Herbert DR. Trefoil factor 2 negatively regulates type 1 immunity against Toxoplasma gondii. J Immunol. 2012 Sep 15; 189(6):3078-84.
  12. Fu CL, Odegaard JI, Herbert DR, Hsieh MH. A novel mouse model of Schistosoma haematobium egg-induced immunopathology. PLoS Pathog. 2012; 8(3):e1002605.
  13. Rani R, Jordan MB, Divanovic S, Herbert DR. IFN-?-driven IDO production from macrophages protects IL-4Ra-deficient mice against lethality during Schistosoma mansoni infection. Am J Pathol. 2012 May; 180(5):2001-8.
  14. Wills-Karp M, Rani R, Dienger K, Lewkowich I, Fox JG, Perkins C, Lewis L, Finkelman FD, Smith DE, Bryce PJ, Kurt-Jones EA, Wang TC, Sivaprasad U, Hershey GK, Herbert DR. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med. 2012 Mar 12; 209(3):607-22.
  15. Butcher BA, Fox BA, Rommereim LM, Kim SG, Maurer KJ, Yarovinsky F, Herbert DR, Bzik DJ, Denkers EY. Toxoplasma gondii rhoptry kinase ROP16 activates STAT3 and STAT6 resulting in cytokine inhibition and arginase-1-dependent growth control. PLoS Pathog. 2011 Sep; 7(9):e1002236.
  16. Rani R, Smulian AG, Greaves DR, Hogan SP, Herbert DR. TGF-ß limits IL-33 production and promotes the resolution of colitis through regulation of macrophage function. Eur J Immunol. 2011 Jul; 41(7):2000-9.
  17. Herbert DR, Orekov T, Roloson A, Ilies M, Perkins C, O'Brien W, Cederbaum S, Christianson DW, Zimmermann N, Rothenberg ME, Finkelman FD. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis. J Immunol. 2010 Jun 1; 184(11):6438-46.
  18. Herbert DR, Yang JQ, Hogan SP, Groschwitz K, Khodoun M, Munitz A, Orekov T, Perkins C, Wang Q, Brombacher F, Urban JF, Rothenberg ME, Finkelman FD. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med. 2009 Dec 21; 206(13):2947-57.
  19. O'Connell AE, Kerepesi LA, Vandergrift GL, Herbert DR, VAN Winkle TJ, Hooper DC, Pearce EJ, Abraham D. IL-4(-/-) mice with lethal Mesocestoides corti infections--reduced Th2 cytokines and alternatively activated macrophages. Parasite Immunol. 2009 Dec; 31(12):741-9.
  20. Nieuwenhuizen N, Herbert DR, Brombacher F, Lopata AL. Differential requirements for interleukin (IL)-4 and IL-13 in protein contact dermatitis induced by Anisakis. Allergy. 2009 Sep; 64(9):1309-18.
  21. Morris SC, Heidorn SM, Herbert DR, Perkins C, Hildeman DA, Khodoun MV, Finkelman FD. Endogenously produced IL-4 nonredundantly stimulates CD8+ T cell proliferation. J Immunol. 2009 Feb 1; 182(3):1429-38.
  22. Khodoun M, Strait R, Orekov T, Hogan S, Karasuyama H, Herbert DR, Köhl J, Finkelman FD. Peanuts can contribute to anaphylactic shock by activating complement. J Allergy Clin Immunol. 2009 Feb; 123(2):342-51.
  23. Herbert DR, Orekov T, Perkins C, Finkelman FD. IL-10 and TGF-beta redundantly protect against severe liver injury and mortality during acute schistosomiasis. J Immunol. 2008 Nov 15; 181(10):7214-20.
  24. Herbert DR, Orekov T, Perkins C, Rothenberg ME, Finkelman FD. IL-4R alpha expression by bone marrow-derived cells is necessary and sufficient for host protection against acute schistosomiasis. J Immunol. 2008 Apr 1; 180(7):4948-55.
  25. Nieuwenhuizen N, Herbert DR, Lopata AL, Brombacher F. CD4+ T cell-specific deletion of IL-4 receptor alpha prevents ovalbumin-induced anaphylaxis by an IFN-gamma-dependent mechanism. J Immunol. 2007 Sep 1; 179(5):2758-65.
  26. Leeto M, Herbert DR, Marillier R, Schwegmann A, Fick L, Brombacher F. TH1-dominant granulomatous pathology does not inhibit fibrosis or cause lethality during murine schistosomiasis. Am J Pathol. 2006 Nov; 169(5):1701-12.
  27. Nieuwenhuizen N, Lopata AL, Jeebhay MF, Herbert DR, Robins TG, Brombacher F. Exposure to the fish parasite Anisakis causes allergic airway hyperreactivity and dermatitis. J Allergy Clin Immunol. 2006 May; 117(5):1098-105.
  28. Herbert DA. Terms without borders: an international approach to terminology. Diagn Cytopathol. 2005 Nov; 33(5):352-5.
  29. Herbert DR, Hölscher C, Mohrs M, Arendse B, Schwegmann A, Radwanska M, Leeto M, Kirsch R, Hall P, Mossmann H, Claussen B, Förster I, Brombacher F. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity. 2004 May; 20(5):623-35.
  30. Kerepesi LA, Nolan TJ, Schad GA, Lustigman S, Herbert DR, Keiser PB, Nutman TB, Krolewiecki AJ, Abraham D. Human immunoglobulin G mediates protective immunity and identifies protective antigens against larval Strongyloides stercoralis in mice. J Infect Dis. 2004 Apr 1; 189(7):1282-90.
  31. Herbert DR, Nolan TJ, Schad GA, Abraham D. The role of B cells in immunity against larval Strongyloides stercoralis in mice. Parasite Immunol. 2002 Feb; 24(2):95-101.
  32. Herbert DR, Nolan TJ, Schad GA, Lustigman S, Abraham D. Immunoaffinity-isolated antigens induce protective immunity against larval Strongyloides stercoralis in mice. Exp Parasitol. 2002 Feb; 100(2):112-20.
  33. Herbert DR, Lee JJ, Lee NA, Nolan TJ, Schad GA, Abraham D. Role of IL-5 in innate and adaptive immunity to larval Strongyloides stercoralis in mice. J Immunol. 2000 Oct 15; 165(8):4544-51.