Tertiary lymphoid structures: chronic inflammatory microenvironments in kidney diseases

Chronic kidney disease is a global health problem with high morbidity and mortality rates. Acute kidney injury substantially increases the risk of chronic kidney disease progression, particularly in the elderly, partly because of prolonged inflammation that exacerbates kidney fibrosis and dysfunction. Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates that develop in non-lymphoid organs during chronic inflammation, such as autoimmune diseases, cancers, and age-related inflammation. Age-dependent TLS formation is observed in various organs, such as the kidneys, bladder, lacrimal glands, and liver, potentially contributing to age-related disorders, including chronic kidney disease progression after acute kidney injury. TLSs contain heterogeneous cell populations, such as T cells, B cells, pro-inflammatory fibroblasts, and blood and lymphatic vessels, which orchestrate TLS development and expansion through intensive cell-cell interactions. Pro-inflammatory fibroblasts within TLSs drive TLS formation by producing various chemokines and cytokines that recruit and activate immune cells. Additionally, the CD153-CD30 signaling pathway between senescence-associated T cells and age-associated B cells, both of which increase with age, are essential for renal TLS maturation and expansion, which could be a promising therapeutic target in kidney injury in aged individuals. TLSs also develop in human kidney diseases, such as various glomerulopathies, transplanted kidneys, and renal cell carcinomas, thereby influencing patient outcomes. This review highlights the recent advances in our understanding of the cellular and molecular mechanisms underlying TLS development and pathogenicity, with a focus on age-dependent TLSs in the kidneys. Furthermore, the clinical relevance of TLSs in human kidney diseases is discussed.