Prof Fiona Powrie FRS

Research Area: Immunology
Scientific Themes: Immunology & Infectious Disease
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The gastrointestinal tract is one of the major sites of immunological challenge to the host immune system. Here the host must be able to mount protective immune responses against invading pathogenic micro-organisms while, at the same time specifically not activating these mechanisms in response to dietary antigens or normal enteric flora. In the intestine, therefore, perhaps more than any other organ, immune reactivity must be tightly regulated to ensure induction of protective and not pathologic responses.

The research interests of the group involve characterisation of the cellular and molecular pathways that control intestinal homeostasis and how these break down in inflammatory bowel disease and colon cancer.

Main areas of research:

  • Analysis of innate responses to intestinal bacteria and how these influence the adaptive immune response
  • Characterisation of intestinal dendritic cell subsets and their contribution to tolerance and immunity in the gut
  • Regulatory T cells and their induction, specificity and function in the intestine
  • Identification of cytokines and downstream signalling pathways that promote intestinal inflammation with particular emphasis on the IL-23/Th-17 immune axis
  • Susceptibility genes that control bacteria-driven colon cancer

Name Department Institution Country
Kevin Maloy Sir William Dunn School of Pathology United Kingdom
John O'Shea National Institute of Arthritis and Musculoskeletal and Skin Diseases United States
Dan Cua Schering Plough Research Institute United States

Schiering C, Krausgruber T, Chomka A, Fröhlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T et al. 2014. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature, Read abstract | Read more

FOXP3(+) regulatory T cells (Treg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function; however, key host factors controlling the Treg response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites, where it functions as an endogenous danger signal, or alarmin, in response to tissue damage. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF)-β1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses. Hide abstract

Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F, Szabady RL, Harrison O, Powrie F. 2013. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med, 210 (5), pp. 917-931. Read abstract | Read more

Patients with inflammatory bowel disease (IBD) have an increased risk of colon cancer. However, the immune cells and cytokines that mediate the transition from intestinal inflammation to cancer are poorly understood. We show that bacteria-induced colon cancer is accompanied by differential accumulation of IL-17(+)IL-22(+) colonic innate lymphoid cells (cILCs), which are phenotypically distinct from LTi and NK-22 cells, and that their depletion in mice with dysplastic inflammation blocks the development of invasive colon cancer. Analysis of the functional role of distinct Type 17 cytokines shows that although blockade of IL-17 inhibits some parameters of intestinal inflammation, reduction in dysplasia and colorectal cancer (CRC) requires neutralization of IL-22 indicating a unique role for IL-22 in the maintenance of cancer in this model. Mechanistic analyses showed that IL-22 selectively acts on epithelial cells to induce Stat3 phosphorylation and proliferation. Importantly, we could detect IL-22(+)CD3(+) and IL-22(+)CD3(−) cells in human CRC. Our results describe a new activity of IL-22 in the colon as a nonredundant mediator of the inflammatory cascade required for perpetuation of CRC, highlighting the IL-22 axis as a novel therapeutic target in colon cancer. Hide abstract

Griseri T, McKenzie BS, Schiering C, Powrie F. 2012. Dysregulated Hematopoietic Stem and Progenitor Cell Activity Promotes Interleukin-23-Driven Chronic Intestinal Inflammation IMMUNITY, 37 (6), pp. 1116-1129. Read abstract | Read more

In interleukin-23 (IL-23)-dependent colitis, there is excessive accumulation of short-lived neutrophils and inflammatory monocytes in the intestine. It is unknown whether this reflects changes in mature cell populations or whether the IL-23-driven colitogenic T cell program regulates upstream hematopoietic stem and progenitor cells (HSPC). Here we have shown dysregulation of hematopoiesis in colitis mediated by inflammatory cytokines. First, there was an interferon-gamma-dependent accumulation of proliferating hematopoietic stem cells in the bone marrow and spleen. Second, there was a strong skew toward granulocyte-monocyte progenitor (GMP) production at the expense of erythroid and lymphoid progenitors. Extramedullary hematopoiesis was also evident, and granulocyte macrophage-colony stimulating factor (GM-CSF) blockade reduced the accumulation of splenic and colonic GMPs, resulting in amelioration of colitis. Importantly, transfer of GMPs exacerbated colitis. These data identify HSPCs as a major target of the IL-23-driven inflammatory axis suggesting therapeutic strategies for the treatment of inflammatory bowel disease. © 2012 Elsevier Inc. Hide abstract

Maloy KJ, Powrie F. 2011. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature, 474 (7351), pp. 298-306. Read abstract | Read more

Intestinal homeostasis depends on complex interactions between the microbiota, the intestinal epithelium and the host immune system. Diverse regulatory mechanisms cooperate to maintain intestinal homeostasis, and a breakdown in these pathways may precipitate the chronic inflammatory pathology found in inflammatory bowel disease. It is now evident that immune effector modules that drive intestinal inflammation are conserved across innate and adaptive leukocytes and can be controlled by host regulatory cells. Recent evidence suggests that several factors may tip the balance between homeostasis and intestinal inflammation, presenting future challenges for the development of new therapies for inflammatory bowel disease. Hide abstract

Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, Powrie F. 2010. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature, 464 (7293), pp. 1371-1375. Read abstract | Read more

The key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (TH17) cells. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-gamma in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-gamma exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-gammat and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-gammat, which controls IL-23R expression, has a functional role, because Rag-/-Rorc-/- mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease. Hide abstract

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