Tissue-Specific Metabolic Reprogramming in Innate Lymphoid Cells and Its Impact on Disease

Overview

Journal Immune Netw

Specialty Allergy & Immunology

Date 2025 Mar 13

PMID 40078781

Authors

Jongho Ham

Wooseok Yang

Hye Young Kim

Affiliations

Soon will be listed here.

Abstract

Recent advances have highlighted the crucial role of metabolic reprogramming in shaping the functions of innate lymphoid cells (ILCs), which are vital for tissue immunity and homeostasis. As tissue-resident cells, ILCs dynamically respond to local environmental cues, with tissue-derived metabolites such as short-chain fatty acids and amino acids directly modulating their effector functions. The metabolic states of ILC subsets-ILC1, ILC2, and ILC3-are closely linked to their ability to produce cytokines, sustain survival, and drive proliferation. This review provides a comprehensive analysis of how key metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid oxidation, influence ILC activation and function. Furthermore, we explore the complex interactions between these metabolic pathways and tissue-specific metabolites, which can shape ILC-mediated immune responses in health and disease. Understanding these interactions reveals new insights into the pathogenesis of conditions such as asthma, inflammatory bowel disease, and cancer. A deeper understanding of these mechanisms may not only advance our knowledge of disease pathogenesis but also lead to the development of novel therapeutic strategies targeting metabolic pathways in ILCs to treat tissue-specific immune disorders.

References

Adamko D, Saude E, Bear M, Regush S, Robinson J . Urine metabolomic profiling of children with respiratory tract infections in the emergency department: a pilot study. BMC Infect Dis. 2016; 16(1):439. PMC: 4994221. DOI: 10.1186/s12879-016-1709-6. View

Cai Y, Li Y, Tang L, Tsoi B, Chen M, Chen H . A new mechanism of vitamin C effects on A/FM/1/47(H1N1) virus-induced pneumonia in restraint-stressed mice. Biomed Res Int. 2015; 2015:675149. PMC: 4331320. DOI: 10.1155/2015/675149. View

Nakajima A, Nakatani A, Hasegawa S, Irie J, Ozawa K, Tsujimoto G . The short chain fatty acid receptor GPR43 regulates inflammatory signals in adipose tissue M2-type macrophages. PLoS One. 2017; 12(7):e0179696. PMC: 5503175. DOI: 10.1371/journal.pone.0179696. View

Wenyang Fu L, Vender R . Systemic role for vitamin d in the treatment of psoriasis and metabolic syndrome. Dermatol Res Pract. 2011; 2011:276079. PMC: 3130965. DOI: 10.1155/2011/276079. View

Yang W, Yu T, Huang X, Bilotta A, Xu L, Lu Y . Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nat Commun. 2020; 11(1):4457. PMC: 7478978. DOI: 10.1038/s41467-020-18262-6. View

Hurrell B, Sakano Y, Shen S, Helou D, Li M, Shafiei-Jahani P . Iron controls the development of airway hyperreactivity by regulating ILC2 metabolism and effector function. Sci Transl Med. 2024; 16(746):eadk4728. DOI: 10.1126/scitranslmed.adk4728. View

Xiao X, Hu X, Yao J, Cao W, Zou Z, Wang L . The role of short-chain fatty acids in inflammatory skin diseases. Front Microbiol. 2023; 13:1083432. PMC: 9932284. DOI: 10.3389/fmicb.2022.1083432. View

Parker M, Barrera A, Wheaton J, Zuberbuehler M, Allan D, Carlyle J . c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program. J Exp Med. 2019; 217(1). PMC: 7037249. DOI: 10.1084/jem.20191030. View

Michelet X, Dyck L, Hogan A, Loftus R, Duquette D, Wei K . Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat Immunol. 2018; 19(12):1330-1340. DOI: 10.1038/s41590-018-0251-7. View

10.

Zang Y, Liu S, Rao Z, Wang Y, Zhang B, Li H . Retinoid X receptor gamma dictates the activation threshold of group 2 innate lymphoid cells and limits type 2 inflammation in the small intestine. Immunity. 2023; 56(11):2542-2554.e7. DOI: 10.1016/j.immuni.2023.08.019. View

11.

Panda S, Kim D, Desai P, Rodrigues P, Sudan R, Gilfillan S . SLC7A8 is a key amino acids supplier for the metabolic programs that sustain homeostasis and activation of type 2 innate lymphoid cells. Proc Natl Acad Sci U S A. 2022; 119(46):e2215528119. PMC: 9674248. DOI: 10.1073/pnas.2215528119. View

12.

Kobayashi T, Lam P, Jiang H, Bednarska K, Gloury R, Murigneux V . Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment. Blood. 2020; 136(26):3004-3017. DOI: 10.1182/blood.2020005602. View

13.

Galle-Treger L, Hurrell B, Lewis G, Howard E, Jahani P, Banie H . Autophagy is critical for group 2 innate lymphoid cell metabolic homeostasis and effector function. J Allergy Clin Immunol. 2019; 145(2):502-517.e5. PMC: 7010567. DOI: 10.1016/j.jaci.2019.10.035. View

14.

Chen Y, Ho H, Tseng C, Chen Y, Wang S, Shieh J . Short-chain fatty acids ameliorate imiquimod-induced skin thickening and IL-17 levels and alter gut microbiota in mice: a metagenomic association analysis. Sci Rep. 2024; 14(1):17495. PMC: 11289318. DOI: 10.1038/s41598-024-67325-x. View

15.

Reinke S, Gallart-Ayala H, Gomez C, Checa A, Fauland A, Naz S . Metabolomics analysis identifies different metabotypes of asthma severity. Eur Respir J. 2017; 49(3). PMC: 5399350. DOI: 10.1183/13993003.01740-2016. View

16.

Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo J, Eberl G . Innate Lymphoid Cells: 10 Years On. Cell. 2018; 174(5):1054-1066. DOI: 10.1016/j.cell.2018.07.017. View

17.

Fu Z, Dean J, Xiong L, Dougherty M, Oliff K, Chen Z . Mitochondrial transcription factor A in RORγt lymphocytes regulate small intestine homeostasis and metabolism. Nat Commun. 2021; 12(1):4462. PMC: 8298438. DOI: 10.1038/s41467-021-24755-9. View

18.

Surace L, Doisne J, Croft C, Thaller A, Escoll P, Marie S . Dichotomous metabolic networks govern human ILC2 proliferation and function. Nat Immunol. 2021; 22(11):1367-1374. PMC: 8553616. DOI: 10.1038/s41590-021-01043-8. View

19.

Doherty T, Khorram N, Lund S, Mehta A, Croft M, Broide D . Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J Allergy Clin Immunol. 2013; 132(1):205-13. PMC: 3704056. DOI: 10.1016/j.jaci.2013.03.048. View

20.

Wilhelm C, Harrison O, Schmitt V, Pelletier M, Spencer S, Urban Jr J . Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection. J Exp Med. 2016; 213(8):1409-18. PMC: 4986525. DOI: 10.1084/jem.20151448. View