Theranostics 2021; 11(1):117-131. doi:10.7150/thno.48624

Research Paper

Tertiary lymphoid organs are associated with the progression of kidney damage and regulated by interleukin-17A

Ran Luo1*, Yichun Cheng1*, Dan Chang1, Tingting Liu1, Liu Liu1, Guangchang Pei1, Nanhui Zhang1, Zufeng Wang1, Kanglin Guo1, Wei Chen2, Ming Li2, Li Fan2, Chunxiu Zhang1, Yueqiang Li1, Wei Dai1, Meiying Zuo1, Yulin Xu1, Ying Yao1, Shuwang Ge1✉, Gang Xu1✉

1. Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
*These authors contributed equally to this paper.

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Citation:
Luo R, Cheng Y, Chang D, Liu T, Liu L, Pei G, Zhang N, Wang Z, Guo K, Chen W, Li M, Fan L, Zhang C, Li Y, Dai W, Zuo M, Xu Y, Yao Y, Ge S, Xu G. Tertiary lymphoid organs are associated with the progression of kidney damage and regulated by interleukin-17A. Theranostics 2021; 11(1):117-131. doi:10.7150/thno.48624. Available from http://www.thno.org/v11p0117.htm

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Abstract

Background: Tertiary lymphoid organs (TLOs) occur after multiple chronic kidney injuries. interleukin-17A (IL-17A) has been reported to associate with the development of TLOs in inflammatory diseases. However, regulation of the renal TLOs and its clinical significance to the pathogenesis of chronic kidney injury are unknown.

Methods: To evaluate the clinical significance and regulation of renal TLOs, we analyzed the progression of patients with kidney damage based on the existence and absence of TLOs in a larger multicenter cohort. We also blocked the recruitment of lymphocyte cells into the kidney by FTY720 (fingolimod) in vivo. Besides, we used aged IL-17A genetic knocked out mice and IL-17A-neutralizing antibody to explore the role of IL-17A in renal TLOs formation.

Results: We demonstrated that renal TLOs of IgA nephropathy patients were associated with disease severity and were independent risk factors for renal progression after adjustment for age, sex, mean arterial pressure, proteinuria and, baseline eGFR and MEST-C score, especially in the early stage. Plasma levels of TLO-related chemokines CXCL13, CCL19, and CCL21 were higher in patients with renal TLOs. Inhibiting the formation of renal TLOs by FTY720 could reduce the intrarenal inflammation and fibrosis, and early intervention was found to be more effective. IL-17A was increased in renal TLOs models, and genetic depletion of IL-17A or treatment with anti-IL-17A antibody resulted in a marked reduction of the TLOs formation as well as alleviation of renal inflammation and fibrosis.

Conclusion: These results indicate that TLOs are associated with the progression of kidney damage and regulated by IL-17A and may be effective targets for the treatment of kidney damage.

Keywords: Tertiary lymphoid organs, kidney damage, IL-17A, progression, inflammation