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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Study Section
Innate Immunity and Inflammation Study Section (III)
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Palker, Thomas J
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Duke University
Schools of Medicine
United States
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Singh, Nina; Inoue, Makoto; Osawa, Ryosuke et al. (2017) Inflammasome expression and cytomegalovirus viremia in critically ill patients with sepsis. J Clin Virol 93:8-14
Kanayama, Masashi; Xu, Shengjie; Danzaki, Keiko et al. (2017) Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin. Nat Immunol 18:973-984
Inoue, Makoto; Chen, Po-Han; Siecinski, Stephen et al. (2016) An interferon-?-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage. Nat Neurosci 19:1599-1609
Kanayama, Masashi; Shinohara, Mari L (2016) Roles of Autophagy and Autophagy-Related Proteins in Antifungal Immunity. Front Immunol 7:47
Kanayama, Masashi; Inoue, Makoto; Danzaki, Keiko et al. (2015) Autophagy enhances NF?B activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity. Nat Commun 6:5779
Inoue, Makoto; Shinohara, Mari L (2015) Hyperinflammation, T cells, and endotoxemia. Oncotarget 6:23040-1
Inoue, Makoto; Shinohara, Mari L (2015) Cutting edge: Role of osteopontin and integrin ?v in T cell-mediated anti-inflammatory responses in endotoxemia. J Immunol 194:5595-8
Kanayama, Masashi; He, You-Wen; Shinohara, Mari L (2015) The lung is protected from spontaneous inflammation by autophagy in myeloid cells. J Immunol 194:5465-71
Inoue, Makoto; Shinohara, Mari L (2014) Clustering of pattern recognition receptors for fungal detection. PLoS Pathog 10:e1003873
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

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