Program Description
Research in the Immunopathogenesis Section is focused on understanding the molecular and immunological mechanisms of fibrosis induced by infection or chronic inflammation.
Arginase-1-expressing macrophages function as suppressor cells during helminth infection. Mice deficient in Arginase-1 in macrophages (Arg1-/flox; LysMcre) fail to downregulate the egg-induced inflammatory response when chronically infected with Schistosoma mansoni. The Arg1-/flox; LysMcre also develop severe liver fibrosis, as shown here by second harmonic emission confocal microscopy. The image shows extensive collagen deposition around schistosome eggs lodged in the liver (see Pesce et al., doi:10.1371/journal.ppat.1000371).
Credit: NIAID
Tissue fibrosis or scarring is a leading cause of morbidity and mortality worldwide. Current health statistics suggest that nearly 45 percent of all natural deaths in the western world are attributable to some type of chronic fibroproliferative disease.
Fibrosis affects nearly all tissues and organ systems. Diseases in which fibrosis is a major cause of morbidity and mortality include the interstitial lung diseases, liver cirrhosis, kidney disease, heart disease, and systemic sclerosis, among others. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate chronic graft rejection in transplant recipients.
Specific aims of the Immunopathogenesis Section include the following:
- Characterize the IL-13-dependent pathway of fibrosis and elucidate the function of novel downstream target genes that are regulated by Th2-associated cytokines, including Arginase-1, Relm-alpha, Muc5ac, and chitinase family proteins
- Understand the link between inflammatory mediators like IL-1, TNF-alpha, and IL-17 and pro-fibrotic cytokines like TGF-beta and IL-13 in various murine models of fibrosis
- Elucidate the role of alternatively activated macrophages (M2) and myeloid-derived suppressor cells in tissue remodeling, inflammation, and fibrosis
- Identify common and unique mechanisms of fibrosis in various organ systems and/or diseases, including persistent asthma, idiopathic pulmonary fibrosis, liver fibrosis, and systemic sclerosis
- Translate findings from mice to humans by establishing relevant preclinical models of fibrosis, so that novel therapies for schistosomiasis and other chronic fibroproliferative disorders might be evaluated quantitatively, in vivo, over time
The group uses transgenic and knockout mice to elucidate the mechanisms of fibrosis and Th2-dependent immunity in vivo.
We are always looking for enthusiastic new investigators to join our group. Contact Dr. Wynn to learn more about the research projects currently available.
Biography
Dr. Wynn obtained his Ph.D. from the University of Wisconsin-Madison Medical School in the department of microbiology and immunology. He is a member of the American Association of Immunologists and the American Society of Tropical Medicine and Hygiene. Dr. Wynn is the recipient of the Oswaldo Cruz Medal and the NIH Certificate of Merit. He joined the Laboratory of Parasitic Diseases in 1991. He became a senior investigator in 2002.
Research Group
Left to right: Luke Barron, Satish Madala, Tom Wynn, Margaret Mentink-Kane, Thiru Ramalingam, Rob Thompson, and Mark Wilson
Selected Publications
Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011 Oct 19;12(11):1035-44.
Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011 Oct 14;11(11):723-37.
Mentink-Kane MM, Cheever AW, Wilson MS, Madala SK, Beers LM, Ramalingam TR, Wynn TA. Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL)-10, IL-12p40, and IL-13Rα2. Gastroenterology. 2011 Aug 22. Epub ahead of print.
Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med. 2011 Jul 4;208(7):1339-50.
Wynn TA, Ramalingam TR. Shedding LIGHT on severe asthma. Nat Med. 2011 May;17(5):547-8.
Wilson MS, Ramalingam TR, Rivollier A, Shenderov K, Mentink-Kane MM, Madala SK, Cheever AW, Artis D, Kelsall BL, Wynn TA. Colitis and intestinal inflammation in IL10-/- mice results from IL-13Rα2-mediated attenuation of IL-13 activity. Gastroenterology. 2011 Jan;140(1):254-64.
Visit PubMed for a complete publication list.
