[要旨]

京都大学大学院医学研究科 分子生体統御学講座 医化学分野
教授 竹内 理 先生

講演タイトル：The Role and Regulation of Immune Cells in Fibrosis: Focusing on Innate Immunity

講演要旨

Fibrosis is characterized by the excessive accumulation of fibrous connective tissues in organs or tissues due to chronic inflammation. Organ fibrosis, such as idiopathic pulmonary fibrosis (IPF), kidney disease, liver disease and heart failure, can lead to multiorgan failure culminating into death. It is well known that the innate and adaptive immune responses participate in the development of progressive fibrotic diseases. Particularly, innate immune cells including neutrophils, monocytes/macrophages and eosinophils are involved in fibrosis and chronic inflammation via production of profibrotic cytokines and mediators that activate myofibroblasts. We recently found that novel innate immune cells, group 2 innate lymphoid cells (ILC2s), also harbor profibrotic function in the lung in the absence of a post-transcriptional regulator of inflammation, Regnase-1. The protein expression levels of Regnase-1 in ILC2s negatively correlated with the ILC2 population in bronchoalveolar lavage fluid in IPF patients. Furthermore, IPF patients with higher ILC2 numbers in peripheral blood exhibited poorer prognosis than those with lower numbers. Mechanistically, studies using mouse models revealed that Regnase-1 acts as an RNase degrading mRNAs encoding a costimulatory molecule ICOS and transcription factors Gata3 and Egr1, which control ILC2 proliferation and expression of fibrosis-associated genes. Thus, Regnase-1 is a critical post-transcriptional regulator of the profibrotic function in ILC2s both in mouse and human. In this seminar, I would like to discuss the contribution of immune cells especially innate immune cells in fibrosis, and their regulatory mechanisms.

京都大学大学院医学研究科 腎臓内科学
京都大学医学部附属病院 腎臓内科
教授 柳田 素子 先生

講演タイトル：Renal microenvironments regulate renal injury, inflammation and fibrosis

講演要旨

Acute kidney injury (AKI) is a common clinical condition in which kidney function rapidly declines, and is associated with high mortality and expensive medical cost. Although kidney function recovers in approximately half of cases of AKI suggesting the existence of intrinsic repair capacity, 10 % of remaining cases die within one month, and the other 40% of cases progress to chronic kidney disease (CKD) or end-stage renal disease. Recent studies further revealed that the severity and frequency of AKI episodes could be risk factors of future CKD, suggesting possible accumulation of tissue damage in the kidney. Thus, kidney injury and repair seem to be dynamically controlled depending on the disease condition, however, the molecules and the cell populations regulating kidney injury and repair remain unclear.

Recently, we identify unique microenvironments orchestrating kidney injury and repair after AKI.

In AKI, the proximal tubules, the most vulnerable segment in the nephrons, are damaged first. After injury, surviving proximal tubules massively proliferate and restore the damaged proximal tubules. At the same time, proximal tubule injury dynamically alters the pre-existing intercellular interaction with fibroblasts, causing fibrosis and renal anemia. Conversely, fibroblasts acquire the capacity to synthesize retinoic acid, which supports proximal tubule regeneration. Additionally, severe proximal tubule injury in aged kidneys recruits hematopoietic cells to form a new distinct microenvironment, tertiary lymphoid tissue (TLT). TLTs, which mainly consist of lymphocytes and fibroblasts, are formed in the chronic phase after AKI, contributing to continuous renal inflammation. Notably, therapeutic strategy targeting TLTs attenuate histological injury and fibrosis in mouse models. The presence of advanced-stage TLTs in the kidney correlates well with the severity of injury and inflammation in human kidney diseases, suggesting the pathological role of TLTs.

As mentioned above, the microenvironments within the kidney regulate kidney damage, repair and inflammation. Further studies analyzing these microenvironments may identify therapeutic targets for kidney disease.

Prof. Matthew James Thomas, Ph.D.
Head of I&RDR Germany, Boehringer Ingelheim Pharma GmbH & Co.KG
Prof. of Pharmacology, Bath University

講演タイトル：Finding drug targets in the immuno-fibrotic niche

講演要旨

Finding drug targets in the immuno-fibrotic niche:

• overview of BI interests in immune senescence & fibrosis
• focus on diseases of interest (PF-ILDs, systemic sclerosis & Crohns disease)
• introduction to ‘immuno-fibrotic niche’, our ‘differential patient biology’ target validation strategy + x3 vignettes of drug hunting strategies for each cell type 

  a）epithelial cell senescence in PF-ILD & our air-liquid interface culture systems used for target validation

  b）different fibroblast populations & intrinsic vs extrinsic senescence exploration via collaboration

  c） senescent prey cells and macrophage efferocytosis in maintaining lung homeostasis

• translational route which will take us from basic research into patients: Precision medicine and our ‘Patient Care Continuum’