This renewal application seeks support for the continuation of our studies designed to elucidate the regulatory programs of dendritic cell subsets that are required for antimicrobial host defenses in the intestine. We recently discovered a cellular circuitry, whereby mucosal DCs interact with the fenestrated capillary vessel system of the small intestine for the sampling of antigens that transition from the blood circulation through the lamina propria into the intestinal lymphatic system and the control of mucosal inflammation. The integration of luminal and circulatory antigen surveillance in the SI indicates that mucosal dendritic cells and macrophages could receive microbial signals that originate outside the intestine and that intestinal pathogen recognition could impact peripheral immune responses. The focus of this proposal will be the foreign nucleic acid recognition pathways in mucosal Zbtb46+ DCs that include distinct classical DC subsets that can induce IL-17 expressing T helper cells (Th17) cells in the mucosal immune system but also drive inducible T regulatory cell development and IL-10 expression. Defining these pivotal mechanisms is important for strategies that can control intestinal inflammation but also for the understanding of the impact of mucosal immune responses on the peripheral immune system and extra intestinal manifestation of inflammatory bowel diseases.

Public Health Relevance

A detailed understanding of sensing of microbial components by dendritic cells in the intestine for the induction of host defenses or tolerance is critical for strategies to curtail mechanisms that impede or exacerbate mucosal immune responses leading to Inflammatory Bowel Diseases. We aim to unravel mechanisms that control the differentiation of mucosal dendritic cells for the regulation of host defenses against viral and bacterial pathogens by elucidating the transcriptional programs that determine T cell polarization in the intestinal mucosa and mesenteric lymph nodes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK068181-08
Application #
8825047
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2004-07-01
Project End
2018-08-31
Budget Start
2014-09-25
Budget End
2015-08-31
Support Year
8
Fiscal Year
2014
Total Cost
$629,128
Indirect Cost
$267,560
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Chiang, Hao-Sen; Zhao, Yun; Song, Joo-Hye et al. (2014) GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses. Nat Immunol 15:63-71
Sundberg, Thomas B; Choi, Hwan Geun; Song, Joo-Hye et al. (2014) Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells. Proc Natl Acad Sci U S A 111:12468-73
Chen, Xinhua; Yang, Guoxun; Song, Joo-Hye et al. (2013) Probiotic yeast inhibits VEGFR signaling and angiogenesis in intestinal inflammation. PLoS One 8:e64227
Chang, Sun-Young; Song, Joo-Hye; Guleng, Bayasi et al. (2013) Circulatory antigen processing by mucosal dendritic cells controls CD8(+) T cell activation. Immunity 38:153-65
Conway, Kara L; Kuballa, Petric; Song, Joo-Hye et al. (2013) Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 145:1347-57
Zhao, Yun; Alonso, Carmen; Ballester, Isabel et al. (2012) Control of NOD2 and Rip2-dependent innate immune activation by GEF-H1. Inflamm Bowel Dis 18:603-12
Sidhu, Maninder; Cotoner, Carmen Alonso; Guleng, Bayasi et al. (2011) Small molecule tyrosine kinase inhibitors for the treatment of intestinal inflammation. Inflamm Bowel Dis 17:2416-26
Diegelmann, Julia; Seiderer, Julia; Niess, Jan-Hendrik et al. (2010) Expression and regulation of the chemokine CXCL16 in Crohn's disease and models of intestinal inflammation. Inflamm Bowel Dis 16:1871-81
Berger, Scott B; Romero, Xavier; Ma, Chunyan et al. (2010) SLAM is a microbial sensor that regulates bacterial phagosome functions in macrophages. Nat Immunol 11:920-7
Fukazawa, Atsuko; Alonso, Carmen; Kurachi, Kiyotaka et al. (2008) GEF-H1 mediated control of NOD1 dependent NF-kappaB activation by Shigella effectors. PLoS Pathog 4:e1000228

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