Abstract
Kidneys are vulnerable organs, and often fail to repair. In particular, renal damage is prolonged and severe in the elderly, but the mechanism behind this was unknown. Recently, we identified a unique microenvironment orchestrating kidney injury and inflammation. Tertiary lymphoid tissues (TLTs), which mainly consist of lymphocytes and fibroblasts, are formed in the chronic phase after injury in aged kidneys, contributing to prolonged inflammation and delayed regeneration. Resident fibroblasts in the kidney play critical roles in the formation of TLTs by acquiring the abilities to produce retinoic acid and homeostatic chemokines, and to support B cell area formation. Notably, therapeutic strategy targeting TLTs attenuates tubular injury and fibrosis in mouse models. Furthermore, TLTs are found in human kidneys, and the presence of advanced-stage TLTs correlates with the severity of kidney injury and inflammation. Specifically, TLTs are commonly found in protocol biopsies of transplanted kidneys, and advanced-stage TLTs are associated with progressive graft dysfunction. Recently, we identifed TNF superfamily CD153-CD30 signaling between two unique age-dependent lymphocyte subpopulations, senescence-associated T (SAT) cells and age-associated B cells (ABCs), as a driver for TLT expansion, and demonstrated that CD153 or CD30 deficiency resulted in attenuated TLT formation with improved inflammation, fibrosis and renal function. Understanding the mechanism of TLT formation may provide clues for the development of therapeutic agents for slowing kidney disease progression.
Published Version
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