Our research projects focus on understanding the dynamic maintenance and transfiguration of homeostasis in the living body. Our goal is to define the homeostasis mechanism under conditions of health and disease. To accomplish this goal, we are trying to clarify the molecular basis of induction and failure of homeostasis by focusing on immune cells in particular mononuclear phagocytes (dendritic cells and macrophages), tissue stem cells, and their functional interplay in the immunological and non-immunological organs, such as skin and intestine. On the basis of our findings, we will further pursue our research in the hope of developing new rational therapies for prevention and treatment of disease.
1. Research on mononuclear phagocytes
1) Discovery of a novel source of mononuclear phagocytes
In 1968, Drs. Ralph van Fruth and Zanvil A. Cohn proposed a concept of mononuclear phagocytes that include monocytes and macrophages. In 1973, Dr. Ralph Steinman discovered dendritic cells (DCs), thereby redefining the mononuclear phagocytes as a population consisting of monocytes, macrophages and also DCs. It has been recently continuing epoch-making discoveries in the field of mononuclear phagocytes and their functions are now beyond classical Immunology and rather extend to broad life phenomenon, e.g. tissue development/regeneration, wound-healing, and establishment of various inflammatory diseases.
DCs consist of conventional DCs (cDCs) and plasmacytoid DCs (pDCs), both of which play critical regulatory roles in the immune system. cDCs exhibit prominent antigen-presenting ability, whereas pDCs are characterized by their capacity to produce large amounts of type I interferons (IFNs). We have discovered the DC progenitors in the mouse bone marrow, and named common DC progenitors (CDPs) (Immunity 2013; Nat Immunol 2007). Interestingly, CDPs are divided into 2 subpopulations. One is M-CSF receptor (R)+ CDPs mainly producing cDCs, and the other M-CSFR-CDPs producing a large number of pDCs. In addition to CDPs, common monocyte/macrophage progenitors, cMoP, identified in the mouse bone marrow and spleen by other group in 2013.
Based on these achievements in mouse, we have been trying to identify human progenitors of mononuclear phagocytes, and most recently succeeded to identify human cMoP (in revision). Human cMoP gives rise to only monocytes but not other hematopoietic cells including DCs. Given that monocytes and monocyte-derived macrophages cause a variety of inflammatory disorders, including metabolic syndromes and tumor development, our studies shed light on possible therapeutic applications for infectious diseases, cancers and autoimmune diseases.
2) Roles of mononuclear phagocytes in inflammatory bowel disease
Breakdown of the intestinal epithelial layer’s barrier function results in the inflow of commensal flora and improper immune responses against the commensal flora, leading to inflammatory bowel disease (IBD) development. Using a mouse dextran sodium sulfate (DSS)–induced colitis model, we showed that commensal Gram-positive bacteria trigger the mobilization of inflammatory monocytes and macrophages into the colon (Mucosal Immunol 2015). TNF-α, a representative cytokine that aggravates colitis and a promising therapeutic target, was predominantly produced by monocytes/macrophages. Among macrophage subpopulations, Ly6c+ macrophages were a major colitogenic subset producing TNF-α. In addition, IFN-γ–Stat1 pathway was required for histone acetylation at the promoter regions of the Tnf loci in macrophages, indicating that IFN-γ–dependent epigenetic regulation instructs the development of colitogenic macrophages. Our study may provide new therapeutic targets, e.g. inhibition of acetyl transferase in macrophage, for treating IBD and colon cancer (in revision).
2. Research on tissue stem cells
1) Understanding of tissue homeostasis and its breakdown on the basis of immune cell-tissue stem cell interplay
We found that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs), and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling, preserves the self-renewal and multi-lineage differentiation capacity of HSCs (Nat Med 2009). Based on this finding, we show that type I IFN preconditioning, without irradiation or DNA alkylating agents, significantly enhanced the HSC engraftment efficiency in wild type (WT) recipient mice (Blood 2013). Based on these achievements, we have further found that physiological levels of type I IFN signaling also affect other tissue stem cells, e.g. intestinal stem cells (ISCs) and hair follicle stem cells (HFSCs). Elucidation of detailed mechanisms is currently in progress.
3. Collaborative research with other institutes
In collaboration with RIKEN, Institute of Physical and Chemical Research, we performed microbiota analysis by 16S rRNA sequencing, and found that there is no significant change in the feces of mice with excess IFN signals specifically in intestinal epithelial cells. As the mice showed defective regeneration capacity of ISCs, we concluded that it is unlikely due to the altered commensal composition (manuscript in preparation).
Immunology lectures in Faculty of Medicine, Masters Degree, and Doctoral Programs, Graduate School Seminar in other universities as a adjunct lecturer, and educational and research guidance for individual graduate students.