Mari L. Shinohara
Immune responses against pathogens are essential for host protection, 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.
The 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 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 to study (1) the roles of PRR in EAE (an animal model of multiple sclerosis), (2) the interplay between immune cells and CNS (central nervous system)-resident cells during EAE and fungal infection, (3) protective and pathogenic mechanisms of immune cells in the lung during fungal infection and inflammation, and (4) the roles of a protein termed osteopontin (OPN), as both secreted (sOPN) and intracellular (iOPN) isoforms, in regulation of immune responses . Although we are very active in EAE to study autoimmunity, other mouse models, such as graft-versus-host disease (GvHD) is ongoing. Cell types we study are mainly DCs, macrophages, neutrophils, and T cells.
Yahara, Yasuhito, Tomasa Barrientos, Yuning J. Tang, Vijitha Puviindran, Puviindran Nadesan, Hongyuan Zhang, Jason R. Gibson, et al. “Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair.” Nat Cell Biol 22, no. 1 (January 2020): 49–59. https://doi.org/10.1038/s41556-019-0437-8.
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.
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.