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Kidney Week

Abstract: PO0634

PD-1 Regulates Group 3 Innate Lymphoid Cells in Renal Fibrosis

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Liang, Zhou, The first Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
  • Zhong, Hao-Jie, Guangdong Medical University, Guangzhou, Guangdong, China
  • Zhu, Chang-Jian, The first Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
  • Zhou, Yi, The first Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
Background

Group 3 Innate Lymphoid Cells (ILC3) belong to a new family of innate effectors, participating in lots of inflammatory and fibrotic diseases. However, limited information exists on the molecular mechanisms regulating these cells. Here, we investigated the expression and function of the immune checkpoint programmed cell death-1(PD-1) in ILC3 during renal fibrosis.

Methods

Unilateral ureteral obstruction (UUO)-induced renal injury tested subsets of ILC3 activities in immune responses and tissue fibrosis. Kidney and intestine were collected to define the frequency, localization and characterization of PD-1+ILC3. Loss/gain-of-ILC3s in UUO mice were designed to investigate their roles in renal fibrosis progression. And the fibrogenic effects of ILC3s and the regulatory activity of PD-1 were determined by in vitro co-culture experiments.

Results

ILC3 were accumulated rapidly in fibrotic kidneys, with surrounding by increasing number of active myofibroblasts, and more interestingly, coincided with a robust depletion from the intestines of mouse models, suggesting a functional recruitment of ILC3 after kidney injury. Moreover, fibrosis was associated with an increase of PD-1 expression in ILCs, and up-expression of PD-1 ligand, PD-L1 was also detected in fibrotic kidney, suggesting a possible involvement of PD-1/PD-L1 pathway. Adoptive transfer of purified intestinal ILC3 into UUO mice significantly enhanced renal fibrosis than those with PBS, whereas PD-1-deficent ILC3 protects kidney from fibrosis. Notably, mice that lacked ILC3s exhibited reduced inflammatory infiltration and decreased fibroblast activation. In vitro studies, direct co-culture of WT-ILC3 with primary renal fibroblasts exacerbates inflammatory response and extracellular matrix production (ECM), which could be blocked by the treatment with neutralizing anti-IL-17A and anti-IL-22 antibodies. Yet co-cultured with PD-1-deficent ILC3 displayed reduced fibrotic activity.

Conclusion

Our findings provided the first evidence that during renal fibrosis, PD-1/PD-L1 axis might play a regulatory role in ILC3 migration and fibrogenesis via producing pro-fibrotic cytokines IL-17A and IL-22.