RESEARCH 2018-01-10T10:22:10+00:00

Trefoil Receptor Identification

Tissue repair and regeneration at the mucosal interface

The most important undertaking of my scientific career to date has been investigation of Trefoil factor biology. Trefoils are a family of three epithelial regenerative factors produced at sites of tissue injury and strongly implicated in regeneration and epithelial restitution. Progress in the field of Trefoil factor biology has been hampered by the lack of a bona fide receptor that has been validated through rigorous in vivo testing. My particular interest is to make our scientific contribution in understanding if and how Trefoils modulate immune cell function in the context of infectious and non-infectious injury. My group has already published and produced several important advances to understanding how Trefoil factors modulate Type 2 and Type 1 immune responses. We have now identified a putative receptor candidate and have one manuscript soon to be published. I was the PI and senior author on all of these publications.

  1. 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.
  2. 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. PMID: 22896633. PMCID: PMC3436937

Macrophage subsets

The role of alternatively activated macrophages in regulating intestinal immunopathology.

Type 2 cytokines interleukin 4 and interleukin 13 along with immunosuppressive cytokines interleukin 10 and transforming growth factor beta (TGF-b) are powerful regulators of tissue macrophage activity, but the molecular mechanisms responsible remain incompletely understood. My work has made important contributions towards our understanding of how the alternatively activated macrophage (M2) phenotype serves to protect against helminth-infection, lung damage and colitic disease. We have also demonstrated how TGF-beta modulates production of the pro-Type 2 cytokine IL-33 to thwart colitic inflammation and emphysematous lung pathology. Thus, maintenance and repair of the mucosal tissue interface relies, at least in part on the macrophage receiving appropriate cytokine signals. This topic is an active area of investigation in my laboratory and we are making novel mouse models to explore these topics in more detail.

  1. Rani R, Jordan MB, Divanovic S, Herbert DR. IFN-gamma-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.
  2. 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.
  3. 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. PMID: 22901754. PMCID: PMC3432431
  4. 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.

Regulation of Type 2 Inflammation

The role of mucosal epithelia in driving host immunity against gastrointestinal worms

How the host eliminates large metazoan parasites from body cavities such as the gastrointestinal lumen remains unclear and a highly contentious topic. Even more so, it remains unclear why humans infected with helminthes show poor signs of protective immunity whereas most experimental model systems using rodents show patent protective immunity following a single prior exposure.  My work has shed light on the critical role served by intestinal epithelial cells in the process of worm expulsion through producing immunoregulatory cytokines and bioactive mediators that interfere with parasite chemosensory locomotion.

  1. 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.
  2. 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. PMID: 23248269. PMCID: PMC3538196
  3. 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.