Ph.D.: 2004, University of Pennsylvania, Philadelphia, PA
Yale University, New Haven, CT
Inflammation, mucosal immunology, cytokines
Office: BMSB 1034
Interleukin-22 (IL-22) is a critical cytokine in modulating tissue responses during inflammation. IL-22 is upregulated in many chronic inflammatory diseases, including inflammatory bowel disease (IBD), making IL-22 biology a potentially rewarding therapeutic target. However, this is complicated by the dual-natured role of IL-22 in inflammation as the cytokine can be protective or inflammatory depending on the disease model. Although scientific interest in IL-22 has increased considerably in the past 10 years, there is still much we do not know about the environmental, cellular and molecular factors that regulate the production and function of this cytokine. A better understanding of IL-22 biology will allow us to develop new or improved therapeutics for treating chronic inflammatory diseases. Our research focuses on the environmental and molecular factors that regulate production of IL-22 from its two major cellular sources, CD4 T cells and group 3 innate lymphocytes (ILC3s).
Numerous cytokines are upregulated in IBD patients, and these immune mediators are at least partially responsible for the inflammatory milieu, leading to ulceration and/or granulomas. The cytokine IL-22 is upregulated in both the sera and inflamed tissue of Crohn’s disease (CD) and ulcerative colitis (UC) patients. Using experimental animal models of IBD, studies have shown that IL-22 is protective to tissues during IBD, through induction of epithelial and stem cell proliferation, antimicrobial peptides and mucins, which compose a mucosal barrier that shields the epithelium. Through effects on the epithelium, IL-22 also modulates the composition of the microbiome which can have an impact on the severity of IBD. In contrast, IL-22 has also been shown to be immunopathogenic in other IBD models, by causing hyperplasia and colonic thickening or increased inflammation. IL-22 is a potential target for drug therapy, either directly or indirectly, by targeting the cytokine itself or upstream factors that regulate its production.
In CD4 T cells, we have shown that IL-22 levels are increased in low oxygen, an environmental cue that often accompanies inflammation (Budda et al. Journal of Immunology. 2016). This upregulation is dependent on the transcription factor hypoxia inducible factor-1a (HIF-1a). We are currently investigating the role of HIF signaling pathways in CD4 T cell differentiation and IL-22 production. We have also examined the effects of low oxygen on how epithelial cells respond to IL-22 and found that hypoxia downregulates epithelial cell responses to IL-22 stimulation (Budda et al. Immunology & Cell Biology. 2017). Our research suggests that IL-22 biology is a complicated integration of signals both in the production of the cytokine and how the target cells respond to the cytokine.
Innate lymphocytes are a broad class of lymphocytes that lack diverse, rearranged antigen-specific receptors. Group 3 innate lymphocytes (ILC3s) are rare immune cells, found primarily in mucosal tissues and a major producer of IL-22. Environmental signals are central for ILC3 activation and the most potent inducers of IL-22 production are IL-23 and IL-1b. We have shown that other environmental signals, including bacterial toxins and man-made glucocorticoids used in IBD therapy, downmodulate ILC3 production of IL-22 (Seshadri et al. PLOS Pathogens. 2017 and Seshadri et al. Journal of Immunology. 2018). Mechanistically, we identified previously unknown molecular circuits involving MAPK and NF-kb signaling that regulate IL-22 production in ILC3s. These data have implications on strategies to modulate either the function of ILC3 or the biological activity of IL-22 during infectious disease or chronic inflammation.
Current Lab Personnel:
Natalie Sullivan, M.S., Research Assistant II
- Zenewicz, L.A., G.D. Yancopoulos, D.M. Valenzuela, A.J. Murphy, M. Karow and R.A. Flavell. 2007. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity. 27(4):647-659.
- Zenewicz, L.A., G.D. Yancopoulos, D.M. Valenzuela, A.J. Murphy, S. Stevens and R.A. Flavell. 2008. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 29(6):947-957.
- Zenewicz, L.A. and R. A. Flavell. 2008. Interleukin-22 and inflammation: Leukin’ through a glass onion. European Journal of Immunology. 32(12):3265-3268.
- Zenewicz, L.A., A. Antov and R.A. Flavell. 2009. CD4 T cell differentiation and inflammatory bowel disease. Trends in Molecular Medicine. 15(5):199-207.
- O’Connor, Jr., W.O., L.A. Zenewicz and R.A. Flavell. 2010. The dual-nature of Th17 cells: Shifting the focus to function. Nature Immunology. 11(6):471-476.
- Kamanaka, M.*, S. Huber*, L.A. Zenewicz*, N. Gagliani, W. O’Conner, Jr., Y.Y. Wan, S. Nakae, Y. Iwakura, L. Hao and R.A. Flavell. 2011. Memory/effector (CD45RBlo) CD4 T cells are controlled directly by IL-10 and cause IL-22 dependent intestinal pathology. The Journal of Experimental Medicine. 208(5): 1027-1040. *equal contribution
- Zenewicz, LA. and R.A. Flavell. 2011. Recent Advances in Interleukin-22 Biology. International Immunology. 23(3):159-163.
- Huber, S., N. Gagliani, L.A. Zenewicz, F. J. Huber, L. Bosurgi, B. Hu, M. Hedi, W. Zhang, W. O’Connor, Jr., A.J. Murphy, D.M. Valenzuela, G.D. Yancopoulos, C. Booth, J.H. Cho, W. Ouyang, C. Abraham and R.A. Flavell. 2012. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature. 491:259-263.
- Zenewicz, L.A., X. Yin, G. Wang, E. Elinav, L. Hao, L. Zhao and R.A. Flavell. 2013. Interleukin-22 deficiency alters colonic microbiota to be transmissible and colitogenic. Journal of Immunology. 190(10): 5306-5312.
- Budda, S.A., A. Girton, J.G. Henderson and L.A. Zenewicz. 2016. The transcription factor HIF-1α controls expression of the cytokine IL-22 in CD4 T cells. Journal of Immunology. 197:2646-2652.
- Budda, S.A., K. Bhattarai, J.L. Alexander and L.A. Zenewicz. 2017. Hypoxic modulation of hepatocyte responses to the cytokine interleukin-22 (IL-22). Immunology & Cell Biology. 95(4):380-387.
- Zenewicz, L.A. 2017. Oxygen Levels and Immunological Studies. Frontiers in Immunology. 8:324. https://www.frontiersin.org/articles/10.3389/fimmu.2017.00324/full
- Seshadri, S., D.S.J. Allan, J.R. Carlyle and L.A. Zenewicz. Bacillus anthracis lethal toxin negatively modulates ILC3 function through perturbation of IL-23-mediated MAPK signaling. PLOS Pathogens. 13(10):e1006690. http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006690
- Budda, S.A. and L.A. Zenewicz. 2018. IL-22 deficiency increases CD4 T cell responses to mucosal immunization. Vaccine. 36(25):3694-3700. https://www.sciencedirect.com/science/article/pii/S0264410X18306182?via%3Dihub
- Seshadri, S., R.L. Pope and L.A. Zenewicz. 2018. Glucocorticoids inhibit group 3 innate lymphocyte IL-22 production. Journal of Immunology. 201:1267-1274. http://www.jimmunol.org/content/early/2018/07/06/jimmunol.1800484
- Zenewicz, L.A. 2018. IL-22: There is a Gap in Our Knowledge. Immunohorizons. 2(6): 198-207. http://www.immunohorizons.org/content/2/6/198
- Chitrakar, A., S.A. Budda, J.G. Henderson, R.C. Axtell and L.A. Zenewicz. 2020. E3 Ubiquitin ligase Von Hippel-Lindau protein promotes Th17 differentiation. Journal of Immunology. 205:1009-1023. https://www.jimmunol.org/content/early/2020/07/18/jimmunol.2000243
For a complete list of publications, see PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=zenewicz+la