DS0402 - Décryptage des fonctions biologiques élémentaires et de leur intégration

Understanding the PROtectiVe Inflammation in DiabEtes – PROVIDE

Understanding the PROtectiVe Inflammation in DiabEtes (PROVIDE Study)

The overall objective of the proposed project is to reveal the physiologic role of inflammation dependent of IRF5 pathways in the adaptation to metabolic stress linked to T2D. Understanding the physiological and the pathological role of the immune system may allow designing personalized treatments promoting a beneficial immune status in patients with T2D.

Connecting diabetes through innate immunity

General Aim of the project:<br />This project deals with our preliminary studies (Dalmas et al. Nature Medicine in press, Kiaf et al unpublished data and (Magalhaes et al., 2015)), which reveal that metabolic inflammation can exert a protective and pathological action towards insulin sensitivity and secretion. We observed that specific pathways controlled by IRF5 in macrophages orchestrate a “protective” immune response in adipose tissue and might have a similar protective action in other metabolic tissues such as liver and pancreatic islets preventing the onset of diabetes. I<br /><br />Specific aims of the project:<br />- Aim 1: To determine the protective immune responses controlled by IRF5 pathways in liver, adipose tissue and pancreas in diet-induced diabetes mouse models (Mouse studies)<br />- Aim 2: To identify the IRF5 molecular actions in the different subsets of tissue macrophages (adipose tissue, liver and pancreas)<br />- Aim 3: To characterize the nature of the innate and adaptive response controlled by IRF5 in liver, adipose tissue and pancreas in diet-induced diabetes mouse models (Mouse studies)<br />- Aim 4: To decipher molecular pathways and cellular cross talk between tissue macrophage IRF5+ cells and MAIT cells in insulin sensitive tissue (liver and adipose tissue) as well as in pancreas (insulin secretory organ) (Mouse study)<br />- Aim 5: To reveal that a protective immune response is corroborated with improvement of glycemic parameters in humans and To integrate clinical and immune data to determine the link between this protective immunity and diabetes progression and complications (Human study)

For this purpose, we will used different regimen and treatment:
Obesity and diabetes through high-fat diet (HFD): The high-fat feeding (60% and 45% fat) is a well-characterised model of obesity-induced insulin resistance. To determine IRF5 pathways on the development of obesity and insulin resistance, the different mouse models (described below) will be subjected to HFD (60% and 45% fat) within 4, 8, 12 and 16 weeks. Adipose tissue, liver and pancreatic ß-cell function over the course of HFD will be investigated in our mouse models.
NAFLD through methionine/choline-deficient diet: The methionine/choline-deficient (MCD) diet will be applied as a well-characterised model for development of non-alcoholic fatty liver disease (NAFLD), inflammation and fibrosis. Using this models, the development of NAFLD will be the main focus, as a major component of T2D pathology in the liver, including hepatic insulin-resistance (IR). The effect of IRF5 myeloid cell-deletion and MAIT cells on the pathogenesis will be determined, in particular with regards to polarisation of the immune response and the immune cell populations.
Liver fibrosis through carbon tetrachloride (CCl4) injection: CCl4 toxicity is a classic murine model of developing aggressive and reproducible fibrosis within 4 weeks of administration. This model will be applied to investigate the role of IRF5 in the development of hepatic fibrosis, as a separate pathological component in the hepatic phenotype seen in IR and T2D. The effect of myeloid cell deletion of IRF5 on development of fibrosis will be investigated with regards to inflammation, remodelling events and polarisation of the immune system.

WT littermate controls and IRF5 MacKO mice were fed with HFD (for 12 and 16 weeks), MCD (for 6 weeks) or treated with CCl4 (for 6 weeks) and then histological analyses of the liver were performed. Eosin and hematoxylin (liver morphology) and red picrosirius (collagen deposition) staining were performed to evaluate the fribogenic and inflammatory modifications upon the described conditions. Interestingly, IRF5 MacKO mice treated with MCD and CCL4 are protected against liver damage (steatosis and fibrosis) compared to WT control mice (Figure 6). Intriguingly, liver steatosis induced by HFD are not significantly different at 12 weeks while at 16 weeks, we can visualize a trend to a decrease of lipid accumulation in IRF5 MacKO compared to WT mice ((Figure 6). Interestingly, the used of our different “metabolic stress” demonstrated a specific contribution of IRF5 in the liver damage. Collectively, our findings strongly support a key role of IRF5 in macrophage during metabolic stress in different organs (liver and adipose tissue).
The “hit” mediated by HFD, MCD or CCl4 might alter macrophages IRF5 actions in specific manner. A deep characterisation of the macrophage phenotype and IRF5 genomic action upon the different conditions is absolutely required.

The above-mentioned data support a role for inflammation in the pathogenesis of type 2 diabetes. Therefore, clinical studies have been initiated and demonstrated that anti-inflammatory treatments including salsalate, TNF and IL-1-antagonism may improve glucose metabolism (Donath, 2014). Therefore treatments addressing inflammation — a cause of the disease — could be used to prevent the progressive decrease in insulin secretion and effectiveness. Although adipose tissue and the pancreatic islets have been the most studied organs, T2D can be manifest in the brain, liver, muscle, heart and periodontal tissues, where there are also signs of inflammation. Treatment may, therefore, also beneficially affect these organs and improve multiple interconnected metabolic circuits. Some anti-inflammatory treatments (such as anti-IL1ß agents) seem to be more effective at improving insulin secretion, whereas others (such as anti-TNF agents and salsalate) may primarily affect insulin-sensitive tissues, probably reflecting the different pathways involved in the immune response during the course of diabetes. Thus, by combining various anti-inflammatory drugs, broader and more efficacious therapeutic strategies could be developed. Judiciously adding or sequentially using these novel antidiabetic treatments could provide a tailored solution for treating inflammation in patients with T2D. Therefore, better characterisation of innate immune response in several diabetic populations could help to increase the care of the patients.

JCI Insight. 2016;1(20):e88689. doi:10.1172/jci.insight.88689.

Type-2 diabetes (T2D) is promoted by multiple mechanisms that underlie a defect in insulin secretion and reduced response to insulin-stimulated glucose uptake in liver, muscle and adipose tissues, known as insulin resistance. These mechanisms include glucotoxicity, lipotoxicity, oxidative stress, endoplasmic reticulum stress and alterations of the gut microbiota. Interestingly, all of these mechanisms are associated with inflammatory response. Clinical studies have demonstrated that anti-inflammatory treatments including IL-1-antagonism, salsalate and probably TNF-antagonism improve glucose metabolism. Some anti-inflammatory treatments may be more effective at improving insulin secretion, while others primarily enhance insulin-sensitivity. Furthermore, there are different mechanisms that engage different branches of immune response during the course of diabetes. Given the heterogeneity of the disease and the complexity of the inflammatory response, optimal anti-inflammatory strategies are a challenge and studies in humans have yielded variable results. However, inflammation is not in itself a disease but a manifestation of a disease. It may have beneficial effects allowing for adaptation to the metabolic stress. Increasing evidence suggests physiological and beneficial effects of the inflammation (called protective immune response) in the adaptive process of increased insulin secretion and reduced insulin resistance. A metabolic inflammatory response consists of four components: inflammatory inducers (such as nutrients), cell sensors (such as macrophages, dendritic cells), inflammatory mediators (such as T cells) and the target tissues (adipose tissue, liver and pancreas) that are affected by inflammatory mediators. The time line of events and the molecular mechanisms that integrate the inflammatory response with metabolic homeostasis at the tissue and systemic levels are still to be characterized in T2D. Recently, we discovered that inflammatory pathways controlled by Interferon Regulatory Factor 5 (IRF5) in macrophages (the sensor cells) orchestrate the immune response towards a pro-diabetogenic program (Dalmas et al. Nature Medicine in press). Interfering with IRF5 pathways (IRF5 macrophage specific KO mice) leads to modification of the innate and adaptive response leading to a healthier metabolic status. Extensive characterization of the IRF5-dependent immune response is required for a better understanding of physiological versus pathological (protective) immune programs involved in T2D (mouse studies). These immune programs will also be validated in different clinical situations (human studies) ie: weight loss, exercise and immune-therapy known to improve diabetes and reduce inflammation.
The overall objective of the proposed project is to reveal the physiologic role of inflammation in the adaptation to metabolic stress linked to T2D. Understanding the physiological and the pathological role of the immune system may allow designing personalized treatments promoting a beneficial immune status in patients with T2D.

Project coordination

Nicolas VENTECLEF (Centre de Recherche des cordeliers, Inserm 1138, Paris, France)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


INSERM_1016 Institut National de la Santé et de la Recherche Médicale
USB Endocrinology, Diabetes & Metabolism University Hospital Basel, Basel, Suisse
INSERM_1138 Centre de Recherche des cordeliers, Inserm 1138, Paris, France

Help of the ANR 406,536 euros
Beginning and duration of the scientific project: October 2015 - 36 Months

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