This proposal seeks to understand the processes driving the increasing prevalence of allergic immune diseases in developing countries. This type of immunity, here termed type 2 immunity, commonly occurs during intestinal helminth infection, and likely underlies the evolution of this host response. We and others have noted the association of cellular constituents of allergic immunity, including eosinophils and alternatively activated macrophages, in mouse visceral adipose tissues, where these cells are required to sustain normal metabolic homeostasis. As shown here, these cell types are maintained in adipose tissues by constitutive activation of innate helper type 2 (ILC2) cells, a novel type of innate lymphoid cell simultaneously reported by this and two other laboratories. This grant seeks to answer the hypothesis that ILC2 cells link mucosal integrity with metabolic homeostasis by attenuating lung and intestinal mucosal inflammation while sustaining systemic energy demands. The grant seeks to pursue this hypothesis in 3 Specific Aims: 1. To establish the role of ILC2 cells in immune and metabolic homeostasis associated with allergic inflammatory challenge;2. To establish the role of ILC2 cells in immune and metabolic homeostasis in animals with genetic deficiencies associated with mucosal inflammation of the lung and intestinal mucosa;and 3. To assess the effects of intestinal parasitic infection on the microbiome and the role of type 2 cytokines in mediating these effects. The novel technical approach involves the use of unique lines of mice established in my laboratory with knockin fluorescent markers containing embedded Cre elements that facilitate cell function-marking, fate-mapping and cell-specific deletion based on function with a high degree of precision. Our approach will open up new lines of investigation in understanding the evolutionary role of ILC2 cells and possibly yield insights into the relationship of allergic immunity, mucosal integrity and systemic energy homeostasis.

Public Health Relevance

Allergic immunity is an increasing problem in developed countries, including the United States, but little is known regarding the basic mechanisms driving this process. This grant proposes that a new type of innate lymphoid cell may link inflammation of the linings of the lung and intestines with how energy is utilized, and thus contribute to our understanding of factors that might be driving epidemics of allergy, inflammation and obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI030663-23
Application #
8578875
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
1991-01-01
Project End
2017-05-31
Budget Start
2013-06-21
Budget End
2014-05-31
Support Year
23
Fiscal Year
2013
Total Cost
$352,655
Indirect Cost
$117,655
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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von Moltke, Jakob; Ji, Ming; Liang, Hong-Erh et al. (2016) Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529:221-5
Molofsky, Ari B; Savage, Adam K; Locksley, Richard M (2015) Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation. Immunity 42:1005-19
Lee, Min-Woo; Odegaard, Justin I; Mukundan, Lata et al. (2015) Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160:74-87
Bando, Jennifer K; Liang, Hong-Erh; Locksley, Richard M (2015) Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. Nat Immunol 16:153-60
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Molofsky, Ari B; Van Gool, Frédéric; Liang, Hong-Erh et al. (2015) Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation. Immunity 43:161-74
Reinhardt, R Lee; Liang, Hong-Erh; Bao, Katherine et al. (2015) A novel model for IFN-γ-mediated autoinflammatory syndromes. J Immunol 194:2358-68
Van Dyken, Steven J; Mohapatra, Alexander; Nussbaum, Jesse C et al. (2014) Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells. Immunity 40:414-24

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