Close Association between Altered Urine–Urothelium Barrier and Tertiary Lymphoid Structure Formation in the Renal Pelvis during Nephritis

Osamu Ichii; Marina Hosotani; Md. Abdul Masum; Taro Horino; Yuki Otani; Takashi Namba; Teppei Nakamura; Elewa Yaser Hosny Ali; Yasuhiro Kon

doi:10.1681/ASN.2021040575

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Visual Abstract

Significance Statement

Tertiary lymphoid structures (TLSs) form in organs exhibiting chronic inflammation. Immune responses to infections, autoimmune responses, or allergic responses may trigger TLS development. We observed urine–urothelium barrier alterations in the renal pelvis of a mouse model and in human subjects with chronic nephritis, with or without infection. Furthermore, urine leaked from the renal lumen into the parenchyma in nephritic mice. This stimulated the production of cytokines/chemokines in renal stromal cells, resulting in TLS development termed “urinary tract–associated lymphoid structures” (UTALSs). UTALS development correlated with chronic nephritis in humans and mice regardless of UTI, thus possibly revealing a novel pathologic mechanism. Elucidation is crucial for better understanding of noninfectious chronic nephritis.

Abstract

Background Kidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathologic features of TLSs, including their formation and association with non-infectious nephritis, are unclear.

Methods RPs from humans and mice that were healthy or had non-infectious chronic nephritis were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures.

Results Regardless of infection, TLSs in the RP, termed urinary tract–associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN-γ as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells via cytokine (IFN-γ, TNF-α) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction via the TNF-α/FOS/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development.

Conclusions TLS formation in the RP is possible and altered urine–urothelium barrier–based UTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.

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