Diabetes: pericyte-orchestrated islet inflammation as a driver of beta-cell failure

Project Information

PIIN_T2D

Grant agreement ID: 101088870

DOI

10.3030/101088870

EC signature date 9 May 2023

Start date 1 July 2023

End date 30 June 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 000 000,00

EU contribution

€ 2 000 000,00

Coordinated by

TEL AVIV UNIVERSITY
Israel

Periodic Reporting for period 1 - PIIN_T2D (Diabetes: pericyte-orchestrated islet inflammation as a driver of beta-cell failure)

Reporting period: 2023-07-01 to 2025-12-31

Summary of the context and overall objectives of the project

Type 2 diabetes (T2D) affects hundreds of millions of people worldwide. It develops when the pancreas cannot produce enough insulin or when the body stops responding to insulin effectively. A major contributor to this condition is the gradual failure of insulin-producing cells, known as beta cells, in the pancreas. While the immune system is typically associated with inflammation and disease, it also plays important roles in supporting healthy tissue function, including in the pancreas.

This ERC-funded project explores how a specialized type of blood vessel cell, called a pericyte, influences the immune environment in the pancreas to support beta cell health. The goal is to understand how pericytes communicate with immune cells under normal conditions, and how this process might become disrupted in diabetes.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To investigate this, we created genetically engineered mouse models that allow us to selectively switch off specific immune signaling pathways in pericytes. These models enabled us to study how pericytes affect the behavior of nearby immune cells and how these interactions, in turn, impact the function of insulin-producing beta cells.

We discovered that pericytes help maintain a balanced immune environment by producing signaling molecules that guide immune cell activity. One of these molecules, CXCL1, prompts immune cells called macrophages to release IL-1beta, a signal that, under healthy conditions, helps maintain the identity and function of beta cells. Additional cytokines produced by pericytes also help attract and support a specific group of macrophages that contribute to beta cell health. When these pericyte-derived signals were disrupted, the balance of immune activity in the pancreas shifted, leading to impaired beta cell function and a reduced ability to regulate blood sugar.

These findings were published in The Journal of Clinical Investigation (2024) and presented at leading international conferences.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

These findings challenge the idea that inflammation in the pancreas is always harmful. Instead, our work reveals that a certain level of controlled immune activity is essential for maintaining healthy insulin production. We refer to this process as pericyte-orchestrated islet inflammation (PIIN).

This is the first time pericytes have been shown to actively control immune signals that are critical for pancreatic function. The concept of PIIN provides a new framework for understanding immune–endocrine communication and opens the door to novel therapies that aim to restore healthy immune signaling in people at risk of developing diabetes.

In addition to these scientific advances, we developed new genetic models that allowed us to selectively study the role of pericytes in immune signaling in vivo. These tools have been instrumental in uncovering how pericytes regulate the local immune environment and support beta cell function, and they continue to support ongoing experiments within the project.

In summary, this project sheds light on the cooperation between blood vessels, immune cells, and insulin-producing cells in the pancreas. By understanding how this communication works in health, we hope to find new ways to prevent or treat diabetes.