The discovery of innate immune receptors has revolutionized the field of innate immunity. An unexpected finding is that innate immune receptor are not only located on the cell membrane, but a majority of these are found intracellularly. This allows cells to detect intracellular perturbation from pathogen-associated molecular patterns (PAMPs) or from damage-associated molecular patterns (DAMPs). Our studies have revealed a novel roles of intracellular innate immune receptor in attenuating inflammation and shaping the microbiome during inflammatory bowel disease (IBD). The central hypothesis is that the bi-directional interplay of inhibitory intracellular innate receptors with the microbiome is a major contributing factor in IBD. Our proposal focuses on the intracellular NLR (nucleotide-binding domain, leucine-rich repeat containing protein, or NOD-like receptor) proteins. While NOD2 remains the most prominent in Crohns? disease, we have focused on the role of other NLRs in colitis. We have data to show that several inhibitory NLR proteins strongly mitigate intestinal inflammation by reducing the activation of immune signaling pathway thus preventing an inflammatory cytokine response that is integral to colitis. This in turn can affect both innate and adaptive immune cells, as well as colon epithelial cells. We have also shown that these inhibitory NLRs affect the microbiome, partly by maintaining bacteria that can contain a pro-inflammatory response. Thus the first goal is to understand the bidirectional interaction of inhibitory NLR and the gut microbiota in mitigating gut inflammation in mice by working with Projects 2, 4 and the Animal Models Core A. Another over-arching goal is to assess the translational relevance of results obtained in mice to humans. Working with Project 3 and the Human Tissue and Genomics Core B, we will analyze patient-derived material to verify the significance of our findings in mice to inflammatory bowel disease patient samples.

Public Health Relevance

This proposal focuses on a two-hit hypothesis where the bidirectional interaction of host genetics affecting innate immune receptor/sensors and the gut microbiota profoundly affects the outcome of inflammatory bowel disease (IBD). We will test this hypothesis in both mouse models and in human IBD samples.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK094779-07
Application #
10018860
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Cronan, Mark R; Matty, Molly A; Rosenberg, Allison F et al. (2018) An explant technique for high-resolution imaging and manipulation of mycobacterial granulomas. Nat Methods 15:1098-1107
Ellermann, Melissa; Sartor, R Balfour (2018) Intestinal bacterial biofilms modulate mucosal immune responses. J Immunol Sci 2:13-18
Pushalkar, Smruti; Hundeyin, Mautin; Daley, Donnele et al. (2018) The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Cancer Discov 8:403-416
Truax, Agnieszka D; Chen, Liang; Tam, Jason W et al. (2018) The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis. Cell Host Microbe 24:364-378.e6
Vázquez-Baeza, Yoshiki; Gonzalez, Antonio; Xu, Zhenjiang Zech et al. (2018) Guiding longitudinal sampling in IBD cohorts. Gut 67:1743-1745
Ho, G-T; Aird, R E; Liu, B et al. (2018) MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. Mucosal Immunol 11:120-130
Keith, Benjamin P; Barrow, Jasmine B; Toyonaga, Takahiko et al. (2018) Colonic epithelial miR-31 associates with the development of Crohn's phenotypes. JCI Insight 3:
Huang, Juin-Hua; Liu, Chu-Yu; Wu, Sheng-Yang et al. (2018) NLRX1 Facilitates Histoplasma capsulatum-Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages. Front Immunol 9:2761
Weiser, Matthew; Simon, Jeremy M; Kochar, Bharati et al. (2018) Molecular classification of Crohn's disease reveals two clinically relevant subtypes. Gut 67:36-42
Sartor, R Balfour; Wu, Gary D (2017) Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. Gastroenterology 152:327-339.e4

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