Intitulé du sujet: Nutrient-Sensitive Myeloid Cells Orchestrate Tissue Immune Response in Health and in Diabetes

Sujet

Codirection:

Nombre de mois: 36 mois

Ecole Doctorale: ED 562 - Bio Sorbonne Paris Cité

Unité de recherche et équipe:

Institut Necker des Infants Malades,

CNRS UMR8253, INSERM U1151,

Université Paris Cité

IMunity and Metabolism of DIABetes (IMMEDIAB)

VENTECLEF Nicolas

Coordonnées de l’équipe:

Secteur: Sciences de la vie / Life Sciences

Langue attendue: Anglais

Niveau de langue attendu: C2

Description

Description du sujet:

The increase in diabetes prevalence has been related to well-recognized risk factors, such as the adoption of a Western lifestyle and an energy-dense diet. Increasing evidence, including our own work, shows that inflammatory and immune pathways are principal and common mediators of the natural course of diabetes, and its complications,under the stimulus of the risk factors. While the detrimental impact of an energy-dense diet on physiology is well established, the impact of nutrients on host systemic and tissue immunity remains surprisingly poorly understood. Perturbations in the intricate immune, nutritional and metabolic cross-talks may contribute to altered metabolic states that govern diabetes. 

Here, we propose an emerging concept supporting that, subpopulations of myeloid cells, particularly circulating monocytes and tissue-resident macrophages, are specialized to sense nutrients including glucose, amino acids and fatty acids to orchestrate systemic and tissue-specific immune responses to maintain metabolic health. Alteration or deregulation of Nutrient-Sensitive myeloid cells functions may initiate or aggravate pathologic inflammatory responses leading to a pro-diabetic status.

Our proposal aims at

i) identifying tissue specific nutrient-sensitive macrophage in mice and humans,

ii) to demonstrate in vivo relevance of these nutrient-sensitive macrophages in tissue immune response and whole-body glucose homeostasis upon energy-dense diets and

iii) characterize postprandial phenotype of nutrient sensitive monocytes induced by low–saturated fat diet and high–saturated fat meals in healthy and diabetic participants. 

Compétences requises:

- Animal experimentation (mouse models)

- Handling and processing of human samples

- Flow cytometry

- Cell biology, cell culture

- Bioinformatics

Références bibliographiques:

1: Vouilloz A, Bourgeois T, Diedisheim M, Pilot T, Jalil A, Le Guern N, Bergas V, Rohmer N, Castelli F, Leleu D, Varin A, de Barros JP, Degrace P, Rialland M,
Blériot C, Venteclef N, Thomas C, Masson D. Impaired unsaturated fatty acid elongation alters mitochondrial function and accelerates metabolic dysfunction-
associated steatohepatitis progression. Metabolism. 2024 Oct 23;162:156051. doi: 10.1016/j.metabol.2024.156051. Epub ahead of print. PMID: 39454822.

2: Guo W, Li Z, Anagnostopoulos G, Kong WT, Zhang S, Chakarov S, Shin A, Qian J, Zhu Y, Bai W, Cexus O, Nie B, Wang J, Hu X, Blériot C, Liu Z, Shen B, Venteclef N, Su B, Ginhoux F. Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease. Immunity. 2024 Oct 8;57(10):2310-2327.e6. doi: 10.1016/j.immuni.2024.08.016. Epub 2024 Sep 23. PMID: 39317200.

3: Julla JB, Girard D, Diedisheim M, Saulnier PJ, Tran Vuong B, Blériot C, Carcarino E, De Keizer J, Orliaguet L, Nemazanyy I, Potier C, Khider K, Tonui DC, Ejlalmanesh T, Ballaire R, Mambu Mambueni H, Germain S, Gaborit B, Vidal- Trécan T, Riveline JP, Garchon HJ, Fenaille F, Lemoine S, Carlier A, Castelli F, Potier L, Masson D, Roussel R, Vandiedonck C, Hadjadj S, Alzaid F, Gautier JF, Venteclef N. Blood Monocyte Phenotype Is A Marker of Cardiovascular Risk in Type 2 Diabetes. Circ Res. 2024 Jan 19;134(2):189-202. doi: 10.1161/CIRCRESAHA.123.322757. Epub 2023 Dec 28. PMID: 38152893.

4: Fumeron F, Velho G, Alzaid F, El Boustany R, Vandiedonck C, Bonnefond A, Froguel P, Potier L, Marre M, Balkau B, Roussel R, Venteclef N. Genetic variants
of interferon-response factor 5 are associated with the incidence of chronic kidney disease: the D.E.S.I.R. study. Genes Immun. 2023 Dec;24(6):303-308. doi:
10.1038/s41435-023-00229-4. Epub 2023 Nov 17. PMID: 37978231; PMCID: PMC10721545.

5: Blériot C, Dalmas É, Ginhoux F, Venteclef N. Inflammatory and immune etiology of type 2 diabetes. Trends Immunol. 2023 Feb;44(2):101-109. doi: 10.1016/j.it.2022.12.004. Epub 2023 Jan 3. PMID: 36604203.

6: Orliaguet L, Ejlalmanesh T, Humbert A, Ballaire R, Diedisheim M, Julla JB, Chokr D, Cuenco J, Michieletto J, Charbit J, Lindén D, Boucher J, Potier C, Hamimi A, Lemoine S, Blugeon C, Legoix P, Lameiras S, Baudrin LG, Baulande S, Soprani A, Castelli FA, Fenaille F, Riveline JP, Dalmas E, Rieusset J, Gautier JF, Venteclef N, Alzaid F. Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling. Nat Commun. 2022 Aug 30;13(1):5089. doi: 10.1038/s41467-022-32813-z. PMID: 36042203; PMCID: PMC9427774.

7: Blériot C, Barreby E, Dunsmore G, Ballaire R, Chakarov S, Ficht X, De Simone G, Andreata F, Fumagalli V, Guo W, Wan G, Gessain G, Khalilnezhad A, Zhang XM, Ang N, Chen P, Morgantini C, Azzimato V, Kong WT, Liu Z, Pai R, Lum J, Shihui F, Low I, Xu C, Malleret B, Kairi MFM, Balachander A, Cexus O, Larbi A, Lee B, Newell EW, Ng LG, Phoo WW, Sobota RM, Sharma A, Howland SW, Chen J, Bajenoff M, Yvan-Charvet L, Venteclef N, Iannacone M, Aouadi M, Ginhoux F. A subset of Kupffer cells regulates metabolism through the expression of CD36. Immunity. 2021 Sep 14;54(9):2101-2116.e6. doi: 10.1016/j.immuni.2021.08.006. Epub 2021 Aug 31. PMID: 34469775.

8: Huang Z, Liang N, Goñi S, Damdimopoulos A, Wang C, Ballaire R, Jager J, Niskanen H, Han H, Jakobsson T, Bracken AP, Aouadi M, Venteclef N, Kaikkonen MU, Fan R, Treuter E. The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages. Mol Cell. 2021 Mar 4;81(5):953-968.e9. doi: 10.1016/j.molcel.2020.12.040. Epub 2021 Jan 26. PMID: 33503407.

9: Drareni K, Ballaire R, Alzaid F, Goncalves A, Chollet C, Barilla S, Nguewa JL, Dias K, Lemoine S, Riveline JP, Roussel R, Dalmas E, Velho G, Treuter E, Gautier JF, Venteclef N. Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion. Cell Rep. 2020 Sep
15;32(11):108141. doi: 10.1016/j.celrep.2020.108141. PMID: 32937117; PMCID: PMC7495095.