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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Palker, Thomas J
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Yale University
Schools of Medicine
New Haven
United States
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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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Iwasaki, Akiko; Medzhitov, Ruslan (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343-53
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Su, Tian; Bondar, Tanya; Zhou, Xu et al. (2015) Two-signal requirement for growth-promoting function of Yap in hepatocytes. Elife 4:
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