Kidney Week

Abstract: FR-PO1215

Dysregulated Intestinal Group 3 Innate Lymphoid Cell (ILC3) Fatty Acid Uptake Mediates Susceptibility to Colitis in Kidney Injury

Session Information

• CKD: Mechanisms - 2
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Tang, Ziwen, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

Ziwen Tang

• Liang, Zhou, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

Zhou Liang, PhD

• Zhu, Chang-Jian, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

Chang-Jian Zhu

• Zhou, Yi, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

Yi Zhou, MD, PhD

Background

Renal injury is commonly accompanied by systematic disorder and remote organ dysfunction. Patients with renal injury often display gastrointestinal symptoms and increased risk of colitis. However, the role and underlying mechanisms of intestinal immunity in mediating renal injury-associated colitis susceptibility have not yet been elucidated.

Methods

Mice that have undergone sham surgery or unilateral ureteral obstruction (UUO) were exposed to dextran sodium sulfate (DSS) to induce experimental colitis. To clarify the contribution of group 3 innate lymphoid cells (ILC3s) in renal injury-associated colitis, ILC3s-deficient mice (Rorc^GFP/GFP mice) or ILC3s-reconstruction mice were exposed to DSS, and then severity of colitis was measured. Single-cell RNA sequencing of intestinal ILC3s was performed to identify their functions and molecular regulatory mechanisms. And flow cytometry was used to detect the corresponding changes in intestinal ILC3s. ILC3s were stained with BODIPY C16 and BODIPY 493/503 to assess their capacity of fatty acid uptake and storage. IL-22 secretion from intestinal ILC3s and the severity of colitis were measured in sham or UUO mice after administration of SSO, a fatty acid uptake inhibitor.

Results

Compared to sham-DSS controls, UUO-DSS mice exhibited exacerbated colitis, faster weight loss, shorter colon length, and higher DAI and histological scores. The exacerbation of colitis also existed in ILC3-complete Rorc^GFP/+-UUO mice, which was abolished in ILC3-deficient Rorc^GFP/GFP mice. In contrast, colitis in UUO-intestinal-ILC3s-reconstituted mice was more severe than in mice receiving sham-intestinal ILC3s. Further analysis revealed that UUO-ILC3s had significantly reduced IL-22 secretion and markedly upregulated fat digestion and absorption pathways, which was confirmed by higher MFI of BODIPY C16 and BODIPY 493/503 than sham-ILC3s. SSO inhibition of UUO-ILC3s fatty acid uptake restored IL-22 expression and prevented UUO-induced colitis exacerbation.

Conclusion

Our data demonstrate that ILC3s are required and sufficient to mediate the susceptibility to colitis associated with renal injury. Mechanistically, upregulation of fatty acid absorption and storage in UUO-ILC3s leads to impaired IL-22 secretion and loss of intestinal barrier protective function.

Funding

• Government Support – Non-U.S.