Makoto Inoue, PhD

Makoto Inoue, Ph.D. is an assistant professor in the Department of Comparative Biosciences and the Neuroscience Program. Prof. Inoue earned his B.S. and M.S. from Tohoku College of Pharmacy and his Ph.D. from Nagasaki University and is a member of The American Association of Immunologists. The long-term objective of the Inoue Lab is to elucidate the interaction between the immune system and nervous system in autoimmune diseases, infectious diseases, and neurodegenerative diseases.

Explain your research in neuroscience; what are you investigating?
The infiltration of peripheral immune cells into the central nervous system (CNS) is critical for the development of neurodegenerative diseases such as multiple sclerosis (MS), which is a debilitating chronic disease of the CNS. Being a heterogeneous complex disease, our current understanding of MS development and its underlying neuroimmune interactions is incomplete, leaving many critical, urgent questions in the field of MS unanswered, such as how neurological degeneration is induced in progressive MS, which patients frequently develop as they age, how MS phenotype switches from remitting type to progressive neurodegenerative type, and how to best prevent and treat it.

Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) impacts immunocompromised individuals who recently recovered from immunosuppression, such as immunocompromised patients who received solid-organ transplants, HIV patients who underwent antiretroviral therapy, MS patients who discontinued immunosuppressive Natalizumab, and even postpartum women. C-IRIS is becoming a major problem in the management of many clinical conditions. A common pathological feature of human patients with C-IRIS is chronic pulmonary disease, lesions and edema in the brain, as well as a high number of CD4+ T cells and upregulation of pro-inflammatory cytokines. Despite these clinical complications, the underlying mechanisms of these pathological manifestations are largely unknown.

In my lab, we study the neuroimmune mechanism of MS using mouse models in the context of disease-contributing factors such as stress, steroid hormone imbalance, and aging. Projects to identify key signaling pathways for the development of C-IRIS are also on-going using newly developed mouse models. The goal of these studies is to fine-tune our understanding of the distinct disease immunopathogenesis of MS reflected by corresponding distinct disease phenotypes, and C-IRIS. The long-term goal of these projects is to contribute to the development of novel and effective therapeutic protocols for disease treatment. 

How are you currently conducting your research?
To best characterize the heterogeneity of MS, we developed unique animal models for MS with and without CNS neurodegeneration. Using these models, we identified how the immune system triggers CNS neuronal damage. Currently, we are further investigating how several etiological factors are involved in MS using these mouse models by combination of immunology, neuroscience, animal behavior, and imaging techniques. 

A major limitation in the understanding of the C-IRIS pathogenesis mechanism is the lack of a reliable animal model. To address this limitation, we established the first reliable and clinically-relevant mouse model of C-IRIS. Using this model, we are investigating the mechanism by which infiltrated immune cell-mediated CNS neuronal damage triggers pulmonary dysfunction, which is a major symptom of C-IRIS patients, by targeting dysregulation of the autonomic system. 

How does being part of the broader Illinois research community support and enhance your work?
It is truly valuable to be part of the broader Illinois research community. It goes without saying that my department, Comparative Biosciences, provides immense support for me as a new investigator and for my lab. Currently, Ko lab (Comparative Biosciences) and our lab are investigating the role of extra-gonad-derived estrogen in MS. To identify therapeutic drugs for MS, the Cheng Lab (Materials Science and Engineering) and our lab are evaluating efficacy of several drugs in unique MS mouse models. Regarding C-IRIS study, Drs. Gee Lau and Lois L. Hoyer (Pathobiology) have given us critical and relevant suggestions. In addition, with Dr. Sivaguru (IGB), we recently developed a new microscopy technique termed Confocal Reflection Supper-Resolution (CRSR), which enables accurate dendritic spine classification and counting in a time-efficient manner under simultaneous visualization of neurons and fluorescence-tagged cells in 3D modality. This technique is not only essential for our study to evaluate neuroimmune interaction in the CNS under disease conditions, but will also be valuable in neuroscience and other related fields. Furthermore, the Neuroscience Program and Immunology Network have also been a valuable commodity for our neuroimmunology study. We are excited to form future collaborations to study neuroimmune interactions in neurodegenerative, autoimmune, and infectious diseases on a multidisciplinary level. 

What led to your interest in this particular area of research?
Neuroscientists and immunologists are encouraged to identify the mechanisms of MS, and to discover critical features and molecules to lead the way in developing effective therapeutic drugs for MS patients. However, MS remains an incurable disease, with treatments that only keep relapses at bay without halting disease progression. Therefore, we are urged to approach the problem with new conceptual ideas for therapeutic targets. By combining my dual background knowledge in neuroscience and immunology, we are investigating mechanisms of neurodegenerative progressive MS as well as detrimental C-IRIS diseases. Importantly and fortunately, we have excellent collaborators to develop new techniques and tools to further our efforts. The amalgamation of a new conceptual idea and novel techniques/tools opens a variety of opportunities to identify unknown mechanisms of MS heterogeneity and C-IRIS development. This fine-tuned understanding is critical to developing new therapeutic strategies for these diseases. The possibility of our research in helping MS patients is a huge motivation for all of us in my laboratory.

In what ways do you envision your work improving society or reaching people?
Our studies use appropriate mouse models and comparison studies to potentiate the identification of disease mechanisms and specific molecules in individual conditions. In addition, studies using new mouse models, new techniques for evaluating CNS neuronal damage, and new drug-delivery techniques have led to the conception of novel ideas for identifying MS and C-IRIS mechanisms. We envision that our discoveries may lead to new therapeutic avenues for MS and C-IRIS patients. Additionally, our models and techniques will be useful for other researchers to further identify the mechanisms of neurodegenerative, autoimmune, and infectious diseases. We want to pursue translational studies in the future based on our work with animal models.