Intestinal homeostasis and its breakdown in IBD. Fiona Powrie
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1 Intestinal homeostasis and its breakdown in IBD Fiona Powrie Translational Gastroenterology Unit Experimental Medicine Division Nuffield Dept of Clinical Medicine University of Oxford Fondation Merieux 10/6/13
2 Maladaptations between the intestinal microbiota and innate and adaptive immune response promote IBD Microbiota changes NOD2 ATG16L1 IL23R, STAT3 IL10 Intestinal barrier function Anti-microbial defense Balance between effector and regulatory T cell responses ** genes associated with IBD risk Innate immunity (NOD2, ATG16L1) Inflammation (IL-23R, STAT3) Adapted from Xavier Nature 2011 Modified from Xavier and Podolsky 2007
3 %Foxp3 - IL10 + among CD4 + T cells Deficiencies in H hepaticus -induced IL-10 leads to IL-23- mediated colitis % IL10 + among CD4 + Foxp3 + T cells C57BL6 Helicobacter hepaticus CD11c Hh DAPI IL-10+Foxp3-3 ** IL-10+Foxp3+ 50 ** Anti-IL10R ** ** IL-23 dependent colitis IL-17-independent 0 Control mln H. Hepaticus mln Control caecum H. hepaticus caecum Control colon H. hepaticus colon 0 Control mln H. Hepaticus mln Control caecum H. hepaticus caecum Control colon H. hepaticus colon Kullberg et al, JEM 2003; Hue et al., JEM 2006
4 The IL-23/Th17 Pathway-distinct mediators may promote particular tissue responses Host defence AMP s Barrier function, repair Naïve T-cell IL-1, IL-6 TGF-β, IL-23 Inflammation GWAS: AS, CD, UC, Psoriasis Models; colitis, joint, skin, uveitis, CNS IL23R RORgt IL-21 IL-22 Th17 cell (CD8, unconv T cells, ILC) IFN-γ TNF-α IL-17A IL-17F GM-CSF Myeloid Cells APCs Stromal Cells
5 IL-17 % Foxp3 among CD4+ IL-23 acts directly on T cells to promote colitis 23R-/- IL23R -/- CD4 + CD45RB hi RAG -/- Foxp3 + 5 p<0.05 WT 23R -/ WT 23R-/- IFN-g Ahern et al., Immunity 2010
6 x 10 2 cells IL-17A <APC-A>: IL-17A Colitis is characterised by high numbers of mature and myeloid progenitor cells-role of GM-CSF? control colitis CD4 + CD45RB hi RAG-/- GR1 neutrophils Inflamm monos Colonic CD4+ Specimen_001_colon 2RR.fcs lymphocytes CD11b GM-CSF <PE-A>: GMCSF 28 N 0 colonic GMP p= control colitic CFU-GM control colitic Marginal CFU activity in the colon ~10X increased during colitis T Griseri et al., Immunity 2012
7 (x10 4 cells) (x10 3 cells) GM-CSF promotes chronic intestinal inflammation colitis colonic neutrophils p= N 0 CD11b + Gr1 hi cells p= N 0 GMP p= RB hi +isotype control RB hi + anti-gm-csf Griseri et al., Immunity 2012
8 Eosinophils and the gastrointestinal tract Rosenberg HF Nat Rev Imm 2013 Eosinophils are abundant throughout the GI tract Present in germ free mice Contributors to the immune response Can mediate tissue damge Increased in acute colitis Increased activation in IBD
9 GM-CSF promotes dysregulated myelopoiesis: Colitogenic role for tissue toxic eosinophils Blood Stem cells BONE MARROW HSC IFN-γ GM-CSF Lamina propria damage Inflammatory monocytes microbiota Eosinophils CLP MEP GMP Neutrophils GM-CSF DC Lymphoid progenitors Erythroid progenitors Myeloid progenitors EMH GMP IFN-γ IL-17 IL-23 Th1/ Th17 Haematopoiesis Chronic Intestinal Inflammation
10 Hue et al., JEM 2006; Buonocore et al., Nature 2010; Boulard JEM 2012; Szabady unpublished Histopathology Score IL-23-driven innate colitis-genetically controlled response to Hh with hallmarks of type 17 response Colitis and colon cancer in 129SvEv C57Bl6 resistant (mapped to Chr3) a-il-23 a-il-17a a-ifng Colon ** 0 RAG 129Rag 129RagIL22 RAG/IL-22KO
11 Thy1 hi SCA-1 + frequency (%) IL23-responsive innate lymphoid cells IL23 induces Th17/Th1 cytokines by a novel population of innate lymphoid cells Innate lymphoid cell Thy1 Lin-ILC IL-23 Colon * IL-23R RORγt SCA-1 IL17A IL22 IFNγ 8 6 IL Buonocore et al., Nature 2010 Control Hh Hh RAG-/- Hh RAG-/- +anti-thy-1
12 IL-23 drives innate colitis through promoting IFN-g and IL-17 by innate lymphoid cells Innate cell involved in the tissue inflammatory response Respond to early microbiallyinduced IL-23 INFLAMMATION Neutrophils IL-23 IL-23 ILC RORgt-dependent cytokine module May be involved in early amplification of the inflammatory response Mf IL-17 IFN-g IL-22 IL-23 ILC Increased Type 17 ILC in CD lesions (Geremia et al., JEM 2011)
13 Type 3 ILC CD127 CD4 CD127 RORγT RORγT C-kit Thy-1 C-kit NKp46 Required for lymphoid organogenesis Dependent on RORgt Lti-like cells produce IL-17 and IL-22 in response to IL-23-host protective in CR infection IL-22 producing ILC Bears NK markers Mediates anti-microbial immunity in intestine CD127 RORγT Thy-1 IL-17, IL-22 and IFN-gamma producing ILC Promote intestinal inflammation Mebius NRI 2003; Eberl G et al., Nat Immunol 2004 ;Takatori et al., JEM 2009; Cella et al., Nature 2009; Buonocore et al., Nature 2010, Sonnenberg et al., Immunity 2011
14 H. Hepaticus-induced invasive colorectal cancer 6w AOM 5 m analysis Highest tumor grade 100% 80% 2 9 % (n=4 ) 60% 75% (n=1 2 ) 7 % (n=1 ) 129 CRC C3B normal 40% 20% 0% No CRC 1 9 % (n=3 ) 129SvEv 6 % (n=1 ) 64% (n=9 ) C 3B Low-grade dysplasia Boulard et al., JEM 2012 High-grade dysplasia CRC
15 Changes in the ILC compartment during H.hepaticus induced cancer Hh+AOM E-cadherin RORg DAPI IL-7Ra DAPI
16 Anti-Thy-1 tx reverses established inflammation and cancerous changes 129 RAG-/- Start of experiment 0w 6-10w H. hepaticus AOM ip 12w-18w Anti-Thy1 after 19w Analysis: Colitis? Cancer? 12w:inflammation cancer Anti-Thy1 100% 80% 60% 40% 62% n=8 91% n=10 CRC dysplasia No CRC 20% 0% 31% n=4 iso anti-thy1
17 IL-22 IL-22 as a pro-tumorigenic factor? IL-22R L-22R1 IL-10R2 Stat3P Survival and growth factor produced by Th22, Nk-22, ILC, LTi IL-22R expression restricted to epithelium Signals through Stat3, which is involved in other CAC models Polymorphisms in IL-22 associated with a 1.46-fold increased risk for development of CRC (Thompson et al. Cancer Causes Control 2010)
18 IL-22 CD4 IL-22 ILC produced IL-22 is acting on the epithelium to promote proliferation 1-3d 6-10w 20w live, CD45 +, lin - live, CD45 +,lin -,Thy1 hi Hh AOM CRC Ab tx 1w Thy1.2 Nkp46 IL-17 Hh+AOM + iso + anti- IL-22 + iso + anti- IL-22 pstat3 Y705 25mm 25mm 25mm 25mm 25mm + anti- IL-17 + anti- IL-6 25mm Cyclin D1
19 IL-22 sustains colon cancer 129 RAG-/- Start of experiment 0w H. hepaticus 6-10w AOM ip 12w-18w Anti-IL-22 after 19w Analysis: Colitis? Cancer? 100% 80% 60% 40% 20% 0% CRC dysplasia no CRC Kirchberger et al., JEM 2013
20 ILC promote colitis and sustain colon cancer through IL-22 production Genetic control of bacteria-driven colon cancer (1.5Mb region on Chr 3-also acts in other models) Functions in haematopietic cells to control early innate response to H. Hepaticus DN Thy1+ ILC accumulate in CRC and mediate a functional role in perpetuation of the disease IL-22 is required for pstat3 in IEC Neutralisation of IL-22 ameliorates established cancer-cell extrinsic control of neoplastic cells IL-22+ T and non-t cells in human CRC-novel therapeutic target (Flavell, Nature 2012;Karin Nature 2012)
21 Inflammatory cytokines contribute to the initiation and perpetuation of bacteria-driven colon cancer H.hepaticus Dysbiosis? AOM pstat3 proliferation CRC DC IL-23 IL-22 IL-17 inflammatory recruitment ROS IL-22 IL-23R + Thy1 hi Sca1 hi cilc Gr cilc Is there an IL-22 signature assoc with spontaneous CRC? Mutations in CAC? Is dysbiosia of the microbiota a contributor to Hh-driven CAC?
22 CRUK Collaborators: D.Littman (NYU) Dan Cua (Merck) Brent Mckenzie (CSL) M. Oukka (Benaroya Inst) Paul Crocker (Dundee) Powrie Lab Chris Scheiring Matt Shale Scott Steward Tharpe Stephanie Kirchberger Olivier Boulard Claire Pearson Allesandra Geremia Carolina Arancibia Tibo Griseri Thomas Krausgruber Philip Ahern Sophia Buonocore Kevin Maloy (SWDSP) Margherita Coccia Simon Travis (TGU) Holm Uhlig (TGU) Daniel Royston (Pathologist)
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