Major Areas of Research
- Type-2 immunity and wound repair
- Asthma and idiopathic pulmonary fibrosis
- Liver fibrosis
- Intestinal fibrosis in inflammatory bowel disease
- Stem cells and tissue regeneration
Below: In many tissues, the tissue-resident macrophage population is derived from the yolk sac and fetal liver during development but is complimented by inflammatory monocytes recruited from the bone marrow after injury. The recruited and resident macrophages undergo marked phenotypic and functional changes in response to DAMPs, PAMPs, growth factors, cytokines, and other mediators released in the local tissue microenvironment. The dominant phenotypic variants depicted here regulate inflammation, tissue repair, regeneration, and resolution. Macrophages produce a variety of factors that stimulate the proliferation, differentiation, and activation of fibroblasts, epithelial cells, endothelial cells, and stem and progenitor cells that facilitate tissue repair. During the later stages of the repair process, they assume a regulatory pro-resolving phenotype that ensures that the tissue-damaging inflammatory response is suppressed and normal tissue architecture is restored. If the process is not controlled effectively, persistent inflammation and/or maladaptive repair processes can lead to tissue-destructive fibrosis. In some cases, the recruited monocytes seed the tissues and adopt a resident macrophage phenotype; however, the mechanisms that restore tissue homeostasis are still under debate. From Wynn and Vannella, Immunity. 2016 Mar 15;44(3):450-62. doi: 10.1016/j.immuni.2016.02.015.
The researchers in the Immunopathogenesis Section (IPS) in LPD/NIAID investigate the immunological and molecular mechanisms of fibrosis, a major cause of morbidity and mortality in many chronic diseases, including asthma, liver cirrhosis, cardiovascular disease, idiopathic pulmonary fibrosis, Crohn’s disease, and ulcerative colitis. The ultimate goal of our research program is to identify novel therapies for fibrotic diseases, for which few viable therapeutic strategies currently exist. The IPS research program relies heavily on transgenic and knockout mouse models to dissect the mechanisms of fibrosis and focuses on three major organs systems, including the liver, lung, and gastrointestinal tract. We also utilize a variety of biopsy tissues obtained from patients suffering from various forms of progressive fibrotic disease.
Fibrotic tissue remodeling is the final common pathological outcome of many chronic inflammatory and infectious diseases. Although the synthesis of extracellular matrix components like collagen is an indispensable and, typically, reversible part of all wound-healing responses, normal tissue repair can evolve into a progressively irreversible fibrotic response if the tissue injury is severe or repetitive or if the wound-healing response itself becomes dysregulated. Indeed, tissue repair and regeneration are critical biological processes that are fundamental to the survival of all living organisms. When tissues are injured during infection or after toxic or mechanical injury, an inflammatory response is induced in response to damage-associated molecular patterns and pathogen-associated molecular patterns released by dead and dying cells and invading organisms, respectively. These molecular triggers induce a complex inflammatory response that is characterized by the recruitment, proliferation, and activation of a variety of hematopoietic and non-hematopoietic cells, including neutrophils, macrophages, innate lymphoid cells, natural killer cells, B cells, T cells, fibroblasts, epithelial cells, endothelial cells, stem cells, and specialized tissue progenitor cells, which together make up the cellular response that orchestrates tissue repair. When the wound-healing response is well organized and controlled, the inflammatory response resolves quickly, and normal tissue architecture is restored. However, if the wound-healing response is chronic or becomes dysregulated, it can lead to the development of pathological fibrosis or scarring, impairing normal tissue function and ultimately leading to organ failure and death. Therefore, wound-healing responses must be tightly regulated. Although fibrogenesis is increasingly recognized as a major cause of morbidity and mortality, there are few—if any—treatment strategies that specifically target the mechanisms of fibrosis, despite the fact that nearly 45 percent of all deaths in the developed world are attributable to fibroproliferative disorders.
The IPS investigates the mechanisms of tissue regeneration and fibrosis and is particularly interested in understanding the role of stem cells and tissue progenitor cells in wound-repair responses more generally. As we were the first group to demonstrate a central and indispensable role for IL-13 in the development of fibrosis, our research program continues to focus on IL-13 biology, with particular emphasis on the role of the IL-13 signaling and decoy receptors. Identifying the key cellular targets of IL-13 has also been emphasized in our research, as we hypothesize that any intervention that disrupts critical steps in the IL-13 response might emerge as a viable therapeutic strategy for fibrosis.
Specific aims of the IPS include the following:
- Identify core mechanisms of fibrosis in various organ systems and/or diseases, including persistent asthma, idiopathic pulmonary fibrosis, liver fibrosis, and inflammatory bowel disease
- Characterize the IL-13 pathway of fibrosis and elucidate the function of novel downstream target genes that are regulated by Th2-associated cytokines
- Understand the link between inflammatory mediators like IL-1, TNF-alpha, and IL-17 and the core pro-fibrotic cytokines TGF-beta and IL-13 in various types of fibrosis
- Elucidate the role of monocyte and macrophage subsets in wound healing, chronic inflammation, and fibrosis progression and resolution
- Investigate the therapeutic potential of macrophages and stem/tissue progenitor cells in tissue regeneration and fibrosis
- Translate findings from mice to humans by establishing relevant preclinical models of fibrosis, so that novel therapies for liver fibrosis and other chronic fibroproliferative disorders might be evaluated
Dr. Wynn is a senior investigator and chief of the Immunopathogenesis Section of the Laboratory of Parasitic Diseases. He also serves as the scientific director of the NIH-Oxford-Cambridge Scholars program, a doctoral training program for outstanding science students committed to biomedical research. He received his Ph.D. from the Department of Microbiology and Immunology at the University of Wisconsin, Madison, Wisconsin in 1991. His laboratory group uses in vivo model systems to elucidate the immunological mechanisms controlling chronic inflammation and fibrosis. He and his colleagues have published over 200 scholarly research papers, reviews, and book chapters in many prestigious journals including Nature, Nature Immunity, Journal of Experimental Medicine, Gastroenterology, Nature Reviews Immunology, Science Translational Medicine, Nature Medicine, and Annual Review of Immunology. He has made seminal contributions to our understanding of the role of IL-13, IL-17A, and macrophages in the progression and resolution of fibrosis in various organ systems and has developed and improved in vivo models to test novel anti-fibrotic drugs. More recently, his laboratory has investigated the role of macrophages, fibroblasts, and tissue progenitor cells in tissue regeneration. Dr. Wynn was elected to fellowship in the American Academy of Microbiology and has received several prestigious awards including the Bailey K. Ashford Medal from the American Society of Tropical Medicine and Hygiene, and the Oswaldo Cruz Medal from the Oswaldo Cruz Foundation. In 2015 and 2016 Thomson Reuters included him among their list of highly cited researchers. He serves as the deputy editor of the Journal of Immunology and Regenerative Medicine, section editor for PLoS Pathogens and the Journal of Leukocyte Biology, and advisory editor for the Journal of Clinical Investigation and Journal of Experimental Medicine. Dr. Wynn has organized several international scientific meetings and collaborates extensively with the pharmaceutical industry.
Pictured from Left to Right: Trey Gieseck, Thiago de Almeida Pereira, David Cantu, Rob Thompson,
Tom Wynn, Josh Sciurba, Kayla Knilans, Kevin Vannella, Casey Rimland,
Rafael de Quieroz Prado, Erik Karmele, Patrick Lin, Kevin Hart
Gieseck RL 3rd, Ramalingam TR, Hart KM, Vannella KM, Cantu DA, Lu WY, Ferreira-González S, Forbes SJ, Vallier L, Wynn TA. Interleukin-13 activates distinct cellular pathways leading to ductular reaction, steatosis, and fibrosis. Immunity. 2016 Jul 19;45(1):145-58.
Vannella KM, Ramalingam TR, Hart KM, deQueiroz Prado R, Sciurba J, Barron L, Borthwick LA, Smith AD, Mentink-Kane M, White S, Thomson RW, Cheever AW, Bock K, Moore I, Fitz LJ, Urban JF Jr., Wynn TA. Acidic chitinase primes the protective immune response to gastrointestinal nematodes. Nat Immunol. 2016 May;17(5):538-44.
Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016 Mar 15;44(3):450-62.
Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia G, Ohri CM, Doran E, Vannella KM, Butler CA, Hargadon B, Sciurba JC, Gieseck RL, Thompson RW, White S, Abbas AR, Jackman J, Wu LC, Egen JG, Heaney LG, Ramalingam TR, Arron JR, Wynn TA, Bradding P. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma.Sci Transl Med. 2015 Aug 19;7(301):301ra129.
Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies.Nat Rev Immunol. 2015 May;15(5):271-82.
Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease.Nature. 2013 Apr 25;496(7446):445-55.
Young DA, Wynn TA, Collins M, Grusby MJ., inventors; Wyeth LCC, The United States of America as represented by the Department of Health and Human Services, assignee. Methods for treating and preventing fibrosis. United States patent US 7,910,105. 2011 Mar 22.
Wynn TA, Chiaramonte MG, Collins M, Donaldson D, Fitz L, Neben T, Whitters MJ, Wood C, inventors; Wyeth, The United States of America as represented by the Department of Health and Human Services, assignee. Treatment of fibrosis by antagonism of IL-13 and IL-13 receptor chains. United States patent US 7,282,206. 2007 Oct 16.
Wynn TA, Chiaramonte MG, Collins M, Donaldson D, Fitz L, Neben T, Whitters MJ, Wood C, inventors; Wyeth, The United States of America as represented by the Department of Health and Human Services, assignee. Treatment of fibrosis by antagonism of IL-13 and IL-13 receptor chains. United States patent US 6,664,227. 2003 Dec 16.
Immunology Advance: How An Immune Molecule Initiates Liver Fibrosis
NIAID research fellow Trey Gieseck, Ph.D., describes results from a mouse study showing how an immune signaling molecule called interleukin-13 initiates liver fibrosis (scarring) from a common parasitic infection. The research lends support to experimental treatments that aim to block interleukin-13 to slow or prevent liver fibrosis.
Immunology Advance: Blocking Alarmins to Treat Long-Term Disease
NIAID research fellow Kevin Vannella, Ph.D., describes results from a mouse study showing how simultaneously blocking three signaling proteins may help treat asthma and liver disease.