Toll-like receptors play a critical role in host defense from infection, as well as in a variety of inflannmatory responses, tissue homeostasis and repair. TLRs induce a highly-complex cellular and transcriptional responses. Specific activation of different responses by TLR family members is mediated by utilization of distinct signaling pathways by different TLRs. This project is focused on the characterization ofthe mechanisms of differential signaling by TLRs that control distinct cellular outputs. We also investigate the mechanisms of negative regulation of TLR induced responses. We are also investigating the mechanisms of TLR induced inflammasome activation and its negative regulation by a variety of anti-inflammatory signals, including IL-10 and adenosine.

Public Health Relevance

Inflammatory responses are critical for the protection from infection and tissue injury. However, inflammation is also a major underlying component of a variety of human diseases. Better understanding of the regulation of inflammation is needed in order to regulate the response in a way that prevents detrimental aspects of inflammation.
The aim of the project is to characterize these regulatory principles and mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI046688-14
Application #
8662082
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Palker, Thomas J
Project Start
1999-10-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Okabe, Yasutaka; Medzhitov, Ruslan (2016) Tissue biology perspective on macrophages. Nat Immunol 17:9-17
Okin, Daniel; Medzhitov, Ruslan (2016) The Effect of Sustained Inflammation on Hepatic Mevalonate Pathway Results in Hyperglycemia. Cell 165:343-56
Luan, Harding H; Medzhitov, Ruslan (2016) Food Fight: Role of Itaconate and Other Metabolites in Antimicrobial Defense. Cell Metab 24:379-87
Iwasaki, Akiko; Medzhitov, Ruslan (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343-53
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Kotas, Maya E; Medzhitov, Ruslan (2015) Homeostasis, inflammation, and disease susceptibility. Cell 160:816-27
Rosenstein, Rachel K; Bezbradica, Jelena S; Yu, Shuang et al. (2014) Signaling pathways activated by a protease allergen in basophils. Proc Natl Acad Sci U S A 111:E4963-71
Nish, Simone A; Schenten, Dominik; Wunderlich, F Thomas et al. (2014) T cell-intrinsic role of IL-6 signaling in primary and memory responses. Elife 3:e01949
Okabe, Yasutaka; Medzhitov, Ruslan (2014) Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157:832-44

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