FOXO1 Orchestrates the Intestinal Homeostasis Via Neuronal Signaling in Group 3 Innate Lymphoid Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2023 Aug 7

PMID 37549024

Authors

Fei Shao

Zhen Liu

Qinglin Wei

Dou Yu

Min Zhao

Xusheng Zhang

Xintong Gao

Zusen Fan

Shuo Wang

Affiliations

Soon will be listed here.

Abstract

The neuro-immune regulation is associated with homeostasis of the intestine. Intestinal group 3 innate lymphoid cells (ILC3s) are tissue-resident lymphocytes whose functions are affected by the intestine niche. However, how a gut neuronal signal coordinates the immune response of ILC3s is largely unknown. Here, we found that cyclic adenosine monophosphate (cAMP) signaling exacerbated the inflammatory response and attenuated the expression level of the transcription factor forkhead box O1 (FOXO1) in ILC3s. Deficiency of FOXO1 drove the hyperactivation of ILC3s and resulted in gut inflammation independently of T cells. Mechanistically, FOXO1 promoted the transcription of neuropeptide receptor VIPR2 and inhibited the transcription of adrenoceptor ADRA2A in ILC3s. FOXO1-related regulation of VIPR2 and ADRA2A signaling balanced the activation of ILC3s under steady condition or during colitis. Moreover, chronic stress elevated cAMP level and downregulated FOXO1 level, exacerbating intestinal inflammation. Our findings reveal that FOXO1 balances the activation of ILC3s via VIP and adrenergic signaling and regulates intestinal homeostasis.

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References

Jarret A, Jackson R, Duizer C, Healy M, Zhao J, Rone J . Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity. Cell. 2020; 180(1):50-63.e12. PMC: 7339937. DOI: 10.1016/j.cell.2019.12.016. View

Lorton D, Bellinger D . Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int J Mol Sci. 2015; 16(3):5635-65. PMC: 4394497. DOI: 10.3390/ijms16035635. View

Abad C, Martinez C, Juarranz M, Arranz A, Leceta J, Delgado M . Therapeutic effects of vasoactive intestinal peptide in the trinitrobenzene sulfonic acid mice model of Crohn's disease. Gastroenterology. 2003; 124(4):961-71. DOI: 10.1053/gast.2003.50141. View

Shen M, Liu Z, Li B, Teng Y, Zhang J, Tang Y . Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells. Cell Death Dis. 2014; 5:e1475. PMC: 4237239. DOI: 10.1038/cddis.2014.400. View

de Kloet E, Joels M, Holsboer F . Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005; 6(6):463-75. DOI: 10.1038/nrn1683. View

Laarakker M, Raai J, van Lith H, Ohl F . The role of the alpha 2A-adrenoceptor in mouse stress-coping behaviour. Psychoneuroendocrinology. 2009; 35(4):490-502. DOI: 10.1016/j.psyneuen.2009.08.014. View

Liu S, Lai L, Zuo Q, Dai F, Wu L, Wang Y . PKA turnover by the REGγ-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis. J Mol Cell Cardiol. 2014; 72:28-38. PMC: 4237316. DOI: 10.1016/j.yjmcc.2014.02.007. View

Wang S, Xia P, Huang G, Zhu P, Liu J, Ye B . FoxO1-mediated autophagy is required for NK cell development and innate immunity. Nat Commun. 2016; 7:11023. PMC: 4820827. DOI: 10.1038/ncomms11023. View

Schwede F, Maronde E, Genieser H, Jastorff B . Cyclic nucleotide analogs as biochemical tools and prospective drugs. Pharmacol Ther. 2000; 87(2-3):199-226. DOI: 10.1016/s0163-7258(00)00051-6. View

10.

Jarade A, Di Santo J, Serafini N . Group 3 innate lymphoid cells mediate host defense against attaching and effacing pathogens. Curr Opin Microbiol. 2021; 63:83-91. DOI: 10.1016/j.mib.2021.06.005. View

11.

Ichiyama K, Gonzalez-Martin A, Kim B, Jin H, Jin W, Xu W . The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression. Immunity. 2016; 44(6):1284-98. PMC: 4918454. DOI: 10.1016/j.immuni.2016.05.015. View

12.

Leong J, Zhou M, Jacob A, Wang P . Aging-related hyperinflammation in endotoxemia is mediated by the alpha2A-adrenoceptor and CD14/TLR4 pathways. Life Sci. 2010; 86(19-20):740-6. PMC: 2859120. DOI: 10.1016/j.lfs.2010.03.009. View

13.

Godinho-Silva C, Cardoso F, Veiga-Fernandes H . Neuro-Immune Cell Units: A New Paradigm in Physiology. Annu Rev Immunol. 2018; 37:19-46. DOI: 10.1146/annurev-immunol-042718-041812. View

14.

Dominguez-Sola D, Kung J, Holmes A, Wells V, Mo T, Basso K . The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program. Immunity. 2015; 43(6):1064-74. DOI: 10.1016/j.immuni.2015.10.015. View

15.

Li J, Sha L, Xu Q . An early increase in glutamate is critical for the development of depression-like behavior in a chronic restraint stress (CRS) model. Brain Res Bull. 2020; 162:59-66. DOI: 10.1016/j.brainresbull.2020.05.013. View

16.

Ahrends T, Aydin B, Matheis F, Classon C, Marchildon F, Furtado G . Enteric pathogens induce tissue tolerance and prevent neuronal loss from subsequent infections. Cell. 2021; 184(23):5715-5727.e12. PMC: 8595755. DOI: 10.1016/j.cell.2021.10.004. View

17.

Wang S, Xia P, Chen Y, Qu Y, Xiong Z, Ye B . Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation. Cell. 2017; 171(1):201-216.e18. DOI: 10.1016/j.cell.2017.07.027. View

18.

Luu T, Sondergaard J, Pena-Perez L, Kharazi S, Krstic A, Meinke S . FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development. Front Immunol. 2022; 13:854312. PMC: 9218573. DOI: 10.3389/fimmu.2022.854312. View

19.

Stone E, Pepper M, Katayama C, Kerdiles Y, Lai C, Emslie E . ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity. 2015; 42(2):239-251. PMC: 4334393. DOI: 10.1016/j.immuni.2015.01.017. View

20.

Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M . Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004; 101(27):10042-7. PMC: 454161. DOI: 10.1073/pnas.0400593101. View