Osteopontin (OPN) is involved in the pathogenesis of a wide variety of inflammatory disorders, including infections, autoimmune diseases, cancer, and other diseases accompanied with inflammation. OPN is primarily considered to be a pro-inflammatory molecule and is generally known to induce immune responses. However, recent studies suggested that OPN occasionally functions as an anti-inflammatory molecule, and how OPN switches its role is entirely elusive. It is critical to know how OPN plays the two-sided role, particularly because OPN attracts attentions as a pharmaceutical target and a disease marker in various diseases. To this end, this proposed study seeks to understand the molecular mechanism by which OPN switches immune responses, and will verify the mechanistic hypothesis with in vivo animal disease models using five lines of OPN mutant mice. Our central hypothesis is: Intracellular OPN (iOPN) is a major player to make OPN?s role switch between pro- inflammatory and anti-inflammatory. Here, OPN has two OPN isoforms, secreted (sOPN) and intracellular (iOPN). In the past, we first succeeded to biochemically confirm the presence of iOPN, and revealed the mechanism of iOPN?s generation and its functions. As a pioneer of the iOPN field, we have been continuously discovering new roles of iOPN, as well as those of sOPN. To study OPN in an isoform-specific fashion, it is important to have cells and mouse lines that exclusively express one of two isoforms. We are currently equipped not only with iOPN and sOPN expression vectors, but we will use multiple lines of OPN mutant mice, which make it possible for us to evaluate the isoform-specific role of OPN in in vivo disease models. The objective of this proposed study is to determine how iOPN functions as an anti-inflammatory molecule; and the long-term goal of this project is to elucidate the roles of iOPN and sOPN in inflammation.

Public Health Relevance

OPN attracts attentions as a pharmaceutical target to treat and diagnose various diseases because of its involvement in the pathogenesis of a wide variety of inflammatory disorders. OPN is a potential pharmaceutical target and a disease marker, but a current critical problem is that we do not know when and how OPN switches from a pro-inflammatory to an anti-inflammatory role.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Love, Dona
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
Aggarwal, Nupur; Barclay, William; Shinohara, Mari L (2018) Understanding mechanisms underlying the pathology of immune reconstitution inflammatory syndrome (IRIS) by using animal models. Curr Clin Microbiol Rep 5:201-209
Shinohara, Mari L (2017) Yes, research matters. PLoS Pathog 13:e1006420
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
Xu, Shengjie; Shinohara, Mari L (2017) Tissue-Resident Macrophages in Fungal Infections. Front Immunol 8:1798
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
Schmidt, Elyse A; Fee, Brian E; Henry, Stanley C et al. (2017) Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages. J Biol Chem 292:4651-4662
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; Danzaki, Keiko; He, You-Wen et al. (2016) Lung inflammation stalls Th17-cell migration en route to the central nervous system during the development of experimental autoimmune encephalomyelitis. Int Immunol 28:463-9
Danzaki, Keiko; Kanayama, Masashi; Alcazar, Oscar et al. (2016) Osteopontin has a protective role in prostate tumor development in mice. Eur J Immunol 46:2669-2678

Showing the most recent 10 out of 22 publications