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Mari Shinohara

Assistant Professor
Research Interest: 
Microbiology and virology
Signal transduction
Research Summary: 
Innate immunity impacts on adaptive immunity during development of diseases, such as cancer, infections, and autoimmune diseases.
Research Description: 

We need to mount a strong immune response against pathogens during infections, but excessive and uncontrolled immune reactions can lead to autoimmunity. How does our immune system keep the balance fine-tuned? This is a central question being asked in my laboratory.

Immune system needs to detect pathogens quickly and effectively. This is performed by the innate immune system, which includes cells such as macrophages and dendritic cells (DCs). Pathogens are recognized by pattern recognition receptors (PRRs) and may be cleared in the innate immune system. However, when pathogens cannot be eliminated by innate immunity, the adaptive immune system participates by exploiting the ability of T cells and B cells. The two immune systems work together not only to clear pathogens effectively but also to avoid collateral damages by from our own immune responses.

In my lab, we use mouse models for infectious and autoimmune diseases to understand the cellular and molecular mechanisms of; pathogen recognition by PRRs in macrophages and DCs, initiation of inflammatory responses in the innate immune system, and the impact of innate immune inflammation on the development and regulation of T cell-mediated adaptive immune responses.

Several projects are ongoing in the lab. They are; (1) elucidating the role of the NLRP3 inflammasome, an innate immune sensor of pathogens and endogenous danger signals, in T-cell mediated pathology of EAE (an animal model of multiple sclerosis), (2) dissecting molecular mechanisms of pathogen recognition throughToll-like receptors (TLRs) and c-type lectin receptors (CLRs) and of downregulating hyperinflammation, (3) molecular and cellular mechanisms in the innate immune system to induce immune tolerance in T cells, and (4) elucidating a role of a protein termed osteopontin (OPN), as both secreted (sOPN) and intracellular (iOPN) isoforms, in regulation of immune responses during infections and tumor development. Although we are very active in EAE to study autoimmunity, other mouse models, such as psoriasis and colitis are ongoing. As for infections, we are interested in fungal infections, which have not been well explored as bacterial and viral infections. Cell types we study are mainly DCs, macrophages, and T cells. By focusing on these immune cell types, we study impacts of infections on the development of autoimmunity.

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation.
Inoue M, Arikawa T, Chen YH, Moriwaki Y, Price M, Brown M, Perfect JR, Shinohara ML.
Proc Natl Acad Sci U S A. 2014. 111:5295-300.

Clustering of pattern recognition receptors for fungal detection.
Inoue M, Shinohara ML.
PLoS Pathog. 2014. 10:e1003873.

NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis.
Inoue M, Williams KL, Gunn MD, Shinohara ML.
Proc Natl Acad Sci U S A. 2012. 109:10480-5.

Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome.
Inoue M, Williams KL, Oliver T, Vandenabeele P, Rajan JV, Miao EA, Shinohara ML.
Sci Signal. 2012. 5:ra38.

Cutting edge: critical role of intracellular osteopontin in antifungal innate immune responses.
Inoue M, Moriwaki Y, Arikawa T, Chen YH, Oh YJ, Oliver T, Shinohara ML.
J Immunol. 2011. 186:19-23.