Kanayama, Masashi, Shengjie Xu, Keiko Danzaki, Jason R. Gibson, Makoto Inoue, Simon G. Gregory, and Mari L. Shinohara. “Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin..” Nat Immunol 18, no. 9 (September 2017): 973–84. https://doi.org/10.1038/ni.3791.
Mari L. Shinohara
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 through Toll-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.
Inoue, Makoto, Po-Han Chen, Stephen Siecinski, Qi-Jing Li, Chunlei Liu, Lawrence Steinman, Simon G. Gregory, Eric Benner, and Mari L. Shinohara. “An interferon-β-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage..” Nat Neurosci 19, no. 12 (December 2016): 1599–1609. https://doi.org/10.1038/nn.4421.
Kanayama, Masashi, Keiko Danzaki, You-Wen He, and Mari L. Shinohara. “Lung inflammation stalls Th17-cell migration en route to the central nervous system during the development of experimental autoimmune encephalomyelitis..” Int Immunol 28, no. 9 (September 2016): 463–69. https://doi.org/10.1093/intimm/dxw013.
Gerriets, Valerie A., Rigel J. Kishton, Amanda G. Nichols, Andrew N. Macintyre, Makoto Inoue, Olga Ilkayeva, Peter S. Winter, et al. “Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation..” J Clin Invest 125, no. 1 (January 2015): 194–207. https://doi.org/10.1172/JCI76012.
Inoue, Makoto, Tomohiro Arikawa, Yu-Hsun Chen, Yasuhiro Moriwaki, Michael Price, Michael Brown, John R. Perfect, and Mari L. Shinohara. “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, no. 14 (April 8, 2014): 5295–5300. https://doi.org/10.1073/pnas.1321427111.