Appropriate development of inflammation is essential to protect hosts against microbial infections, but inflammation can occasionally overshoot and cause collateral damages in hosts. Such damages can be deadly. In this proposal, we focus on an unconventional regulation of over-reacted innate immunity by adaptive immunity. Molecular mechanism of such regulation is currently elusive and unexplored. Upon successful completion of this study, we expect to understand the novel mechanism by which adaptive immunity induces innate tolerance. The mechanistic understanding will have a significant impact on developing not only optimal therapies against acute hyper-inflammation but also vaccines and therapies against chronic inflammation, including autoimmune diseases. Our preliminary data suggested excessive TNF production by macrophages and DCs is suppressed by T cells through CD40-CD40L interaction. We further identified that, osteopontin (OPN), a protein largely known as a pro-inflammatory molecule, unexpectedly plays a regulatory role in suppressing TNF expression in macrophages by IRAK1-mediated IL-10 production. The OPN isotype that plays the regulatory role is not the canonical secreted OPN (sOPN) but a novel intracellular isoform of OPN (iOPN). Based on our preliminary data, the central hypothesis of this study is: iOPN mediates crosstalk between CD40 (stimulated by T cells) and TLR4 (stimulated by a microbial ligand) in macrophages and DCs to suppress TNF production generated by TLR4 stimulation. In this R21 proposal, we plan to test the hypothesis.

Public Health Relevance

Our immune system is equipped with various mechanisms, which protect us from microbial infections. However, such protective mechanisms could overshoot and cause excessive inflammation and tissue damages. The outcomes could be lethal, such as sepsis. Here, our body should have mechanisms to control hyper-inflammation, but they are still largely elusive. In this proposal, we plan to prove the concept of our molecular mechanistic model that may plays a role in controlling hyper inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI103584-01A1
Application #
8635927
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$211,950
Indirect Cost
$76,950
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Inoue, Makoto; Arikawa, Tomohiro; Chen, Yu-Hsun et al. (2014) T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation. Proc Natl Acad Sci U S A 111:5295-300
Wang, Bin; Rao, Yan-Hua; Inoue, Makoto et al. (2014) Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nat Commun 5:3479