Scientific Research Report: The Protective Role of Integrin α4β7 and Type 2 Innate Lymphoid Cells in Nephritis

In a recent study, an international research team led by Dr. Seungwon Ryu revealed the critical protective role of integrin α4β7 and Type 2 Innate Lymphoid Cells (ILC2s) in nephritis caused by Systemic Lupus Erythematosus (SLE). The study was published in the journal “Cellular & Molecular Immunology,” with the research team comprising members from various universities and research institutions in Korea, including Gachon University, Incheon National University, and Seoul National University.

Research Background

ILC2s, members of the innate lymphoid cell family, have recently been identified as important regulators of inflammation and tissue repair in various organs. Although their role in nephritis (including lupus nephritis) has been partially revealed, the mechanisms of ILC2 adhesion and migration in the kidney remain unclear. Furthermore, the residence and function of ILC2s in the kidney through integrin α4β7 warrant further investigation. Previous studies have shown that ILC2s participate in renal inflammation regulation by secreting cytokines and can alleviate kidney injury in mouse salt injury models through adaptive transplantation. However, the specific mechanism of ILC2s in lupus-induced nephritis has not been clearly defined.

Research Content Overview

This study primarily analyzed the adhesion and migration behavior of ILC2s in the kidney under healthy and pathological conditions (especially lupus nephritis) and explored the key role of integrin α4β7 in this process.

Research Methods

The research team used two mouse models: the naturally occurring lupus MRL-lpr mouse model and the TLR7 agonist-induced lupus mouse model. The research process was as follows:

1. Selection and treatment of mouse models:

   • MRL-lpr mouse model: Young mice (5-8 weeks old) served as the control group, while older mice (>16 weeks old) served as the pathological group.
   • Imiquimod (IMQ) induced model: 6-8 week old female BALB/c mice, with IMQ cream applied to the ears three times a week for 7 weeks.

2. Tissue samples and cell isolation:

   • Mice were dissected under anesthesia, kidney tissues were collected, and ILC2s and other cell types in the kidney were analyzed through enzymatic digestion and flow cytometry.

3. Single-cell RNA sequencing (scRNA-seq):

   • ILC2s from young and old MRL-lpr mouse kidneys were enriched and subjected to single-cell RNA sequencing to analyze the gene expression characteristics of ILC2s.

Main Experimental Results

1. The key role of integrin α4β7 in renal ILC2s:

   • ILC2s in healthy kidneys highly express integrin α4β7, which binds to VCAM-1, E-cadherin, and fibronectin on renal structural cells, ensuring ILC2s reside in the kidney.
   • In lupus nephritis, TLR7/9 signaling downregulates integrin α4β7 expression in ILC2s, causing ILC2s to migrate from the kidney to peripheral blood.

2. Integrin downregulation leads to increased inflammation:

   • After integrin α4β7 downregulation, ILC2s’ ability to secrete the reparative cytokine amphiregulin (AREG) decreases, promoting local inflammatory responses.
   • IL-33 treatment can upregulate integrin α4β7 and AREG expression in ILC2s, improving ILC2 survival and alleviating inflammation caused by lupus nephritis.

Experimental Conclusions and Significance

This study reveals that regulating ILC2s residence and function in the kidney through integrin α4β7 is a key mechanism for modulating inflammatory responses in lupus nephritis. ILC2s interact with renal structural cells through integrin α4β7, maintaining their residence in the kidney and inhibitory effect on inflammatory responses. The secretion of the reparative cytokine AREG by ILC2s is crucial in inflammation regulation. The newly discovered TLR7/9-IL-33-Integrin α4β7 axis provides a new perspective on the regulation of ILC2s residence and function in nephritis.

Research Highlights

• Key role of integrin α4β7: Systematically revealed for the first time the critical role of integrin α4β7 in ILC2s residence in the kidney and its expression regulation mechanism in lupus nephritis.
• IL-33 treatment: IL-33 has the potential to serve as a new therapeutic strategy for lupus nephritis by regulating integrin expression and enhancing the secretion of reparative factors by ILC2s.
• Role of AREG in renal inflammation: Clarified the inhibitory role of ILC2-derived AREG in renal inflammation and tissue repair.

Application Value

This study not only reveals the mechanism of ILC2s in lupus nephritis at the basic research level but also provides new ideas for clinical treatment of lupus nephritis by regulating ILC2s adhesion and function. In the future, it is expected to develop cell therapies and drugs based on integrin regulation or IL-33 treatment to better address renal inflammation issues.

This research, through multiple experimental models and cutting-edge technical means, deeply explored the pathological mechanism of lupus nephritis and its potential therapeutic strategies, providing important scientific evidence and new ideas for understanding and treating renal inflammation.