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

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

J Am Soc Nephrol. 2022 Jan;33(1):88-107. doi: 10.1681/ASN.2021040575. Epub 2021 Oct 22.

Authors

Osamu Ichii^{1

2}, Marina Hosotani³, Md Abdul Masum^{1

4}, Taro Horino⁵, Yuki Otani¹, Takashi Namba¹, Teppei Nakamura^{1

6}, Elewa Yaser Hosny Ali^{1

7}, Yasuhiro Kon¹

Affiliations

¹ Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
² Laboratory of Agrobiomedical Science, Faculty of Agriculture, Hokkaido University, Sapporo, Japan.
³ Laboratory of Anatomy, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
⁴ Department of Anatomy, Histology and Physiology, Faculty of Animal Science and Veterinary Medicine, Sher-e-Bangla Agricultural University, Dhaka, Bangladesh.
⁵ Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan.
⁶ Department of Biological Safety Research, Food Research Laboratories, Chitose, Japan.
⁷ Department of Histology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.

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.

Keywords: chemokine; chronic inflammation; fibroblast; histopathology; immunology and pathology; kidney anatomy; nephritis; pathology; pathophysiology of renal disease and progression; pyelonephritis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Case-Control Studies
Chronic Disease
Disease Models, Animal
Female
Humans
Kidney Pelvis / metabolism
Kidney Pelvis / pathology*
Male
Mice
Mice, Inbred C57BL
Middle Aged
Nephritis / etiology*
Nephritis / metabolism
Nephritis / pathology*
Tertiary Lymphoid Structures / pathology*
Urine
Urothelium / metabolism
Urothelium / pathology*