Crohn's disease and ulcerative colitis (inflammatory bowel disease, IBD) are important clinical problems, but molecular targets for therapeutic immune intervention remain elusive. Intestinal dendritic cells (DCs) and macrophages (M?s) play a pivotal role in mediating mucosal tolerance and suppressing inflammation. In IBD, these cells lose their tolerogenic properties resulting in uncontrolled intestinal inflammation. However, the molecular pathways that program these cells to a tolerogenic state rather than to an inflammatory state are not known. We have identified a new and previously unsuspected role for the ?-catenin signaling pathway as a key molecular regulator of tolerogenic phenotype in intestinal DCs and M?s. ?-catenin is downstream of three sets of ligands widely expressed in the gut (TLR ligands, wnt ligands and E-cadherin), and ablation of ?-catenin in these cells causes loss of tolerance. The current proposal will focus on the mechanistic role of the ?-catenin pathway in regulating key downstream effector mechanisms, and test its relevance in in vivo models of colitis and oral tolerance.
Specific aims i n the current proposal are (i) to understand the molecular mechanisms by which ?-catenin/TCF pathway regulates the expression of three key immune regulatory genes - IL-10, RALDH and IDO - in intestinal DCs and M?s (Aim 1), (ii) to understand the functional and biological role of this pathway in intestina DCs and M?s in T regulatory cell differentiation and expansion (Aim 2), and (iii) their ability to limit intestinal inflammation and promote oral tolerance (Aim 3). The successful completion of the proposed studies will provide new mechanistic insights into how the ?-catenin/TCF pathway in intestinal DCs and M?s regulates a balance between tolerance and inflammatory responses, and will provide a mechanistic rationale for targeting this pathway in IBD. Pharmacological activators of ?-catenin pathway already exist, and more are in development and the proposed studies will provide a rationale for the development of an entirely new class of agents that may have significant therapeutic impact in treating IBD.

Public Health Relevance

A fundamental puzzle in mucosal immunology is how the immune system decides between tolerogenic response versus inflammatory response against commensals, pathogens and harmless food antigens. Intestinal dendritic cells (DCs) and macrophages (M?s) play a central role in this complex decision making process, but the molecular pathways that program these cells are not known. We have identified a novel molecular pathway that programs intestinal dendritic and M?s to a tolerogenic phenotype and limits intestinal inflammation. The information gained from these studies will provide will provide a rationale for the development of an entierly new class of agents that may have significant therapeutic impact in treating inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK097271-01
Application #
8421463
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2012-09-20
Project End
2017-06-30
Budget Start
2012-09-20
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$326,250
Indirect Cost
$108,750
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Ranganathan, Punithavathi; Shanmugam, Arulkumaran; Swafford, Daniel et al. (2018) GPR81, a Cell-Surface Receptor for Lactate, Regulates Intestinal Homeostasis and Protects Mice from Experimental Colitis. J Immunol 200:1781-1789
Swafford, Daniel; Shanmugam, Arulkumaran; Ranganathan, Punithavathi et al. (2018) Canonical Wnt Signaling in CD11c+ APCs Regulates Microbiota-Induced Inflammation and Immune Cell Homeostasis in the Colon. J Immunol 200:3259-3268
Pathania, Rajneesh; Ramachandran, Sabarish; Mariappan, Gurusamy et al. (2016) Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth. Cancer Res 76:3224-35
Suryawanshi, Amol; Tadagavadi, Raghu K; Swafford, Daniel et al. (2016) Modulation of Inflammatory Responses by Wnt/?-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer. Front Immunol 7:460
Manoharan, Indumathi; Suryawanshi, Amol; Hong, Yuan et al. (2016) Homeostatic PPAR? Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine. J Immunol 196:4739-49
Kandasamy, Matheswaran; Suryawanshi, Amol; Tundup, Smanla et al. (2016) RIG-I Signaling Is Critical for Efficient Polyfunctional T Cell Responses during Influenza Virus Infection. PLoS Pathog 12:e1005754
Swafford, Daniel; Manicassamy, Santhakumar (2015) Wnt signaling in dendritic cells: its role in regulation of immunity and tolerance. Discov Med 19:303-10
Pathania, Rajneesh; Ramachandran, Sabarish; Elangovan, Selvakumar et al. (2015) DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat Commun 6:6910
Suryawanshi, Amol; Manicassamy, Santhakumar (2015) Tumors induce immune tolerance through activation of ?-catenin/TCF4 signaling in dendritic cells: A novel therapeutic target for cancer immunotherapy. Oncoimmunology 4:e1052932
Suryawanshi, Amol; Manoharan, Indumathi; Hong, Yuan et al. (2015) Canonical wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation. J Immunol 194:3295-304

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