Toll-like receptors play a critical role in host defense from infection, as well as in a variety of inflannmatoryresponses, tissue homeostasis and repair. TLRs induce a highly-complex cellular and transcriptionalresponses. Specific activation of different responses by TLR family members is mediated by utilization ofdistinct signaling pathways by different TLRs. This project is focused on the characterization ofthemechanisms of differential signaling by TLRs that control distinct cellular outputs. We also investigate themechanisms of negative regulation of TLR induced responses. We are also investigating the mechanisms ofTLR 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, inflammationis also a major underlying component of a variety of human diseases. Better understanding of the regulationof inflammation is needed in order to regulate the response in a way that prevents detrimental aspects ofinflammation.
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 #
4R37AI046688-11
Application #
7994920
Study Section
Special Emphasis Panel (NSS)
Program Officer
Palker, Thomas J
Project Start
1999-10-01
Project End
2016-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
11
Fiscal Year
2011
Total Cost
$413,278
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
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Luan, Harding H; Medzhitov, Ruslan (2016) Food Fight: Role of Itaconate and Other Metabolites in Antimicrobial Defense. Cell Metab 24:379-387
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Kotas, Maya E; Medzhitov, Ruslan (2015) Homeostasis, inflammation, and disease susceptibility. Cell 160:816-27
Ip, W K Eddie; Medzhitov, Ruslan (2015) Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat Commun 6:6931
Iwasaki, Akiko; Medzhitov, Ruslan (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343-53
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