2. Academic Validation
  3. The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function

The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function

  • Cell Rep. 2025 Apr 22;44(4):115456. doi: 10.1016/j.celrep.2025.115456.
Diogo Fonseca-Pereira 1,  Sena Bae 1,  Slater L Clay 1,  Monia Michaud 1,  Meghan H MacDonald 1,  Jonathan N Glickman 2,  Wendy S Garrett 3
Affiliations

Affiliations

  • 1 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA.
  • 2 Gastrointestinal Pathology, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: wgarrett@hsph.harvard.edu.
PMID: 40120107 DOI: 10.1016/j.celrep.2025.115456
Abstract

Group 3 innate lymphoid cells (ILC3s) are tissue-resident cells that sense environmental cues, control infections, and promote tissue homeostasis at mucosal surfaces. The metabolic sensor liver kinase B1 (LKB1) integrates intracellular stress, metabolism, and mitochondrial function to promote the development and effector functions of a variety of immune cells; however, the role of LKB1 in ILC3 function was unknown. Here, we show that LKB1 is crucial for adult ILC3 homeostasis, cytokine production, and mitochondrial function. ILC3-specific LKB1 deletion resulted in a reduced number of ILC3s and interleukin-22 (IL-22) production. LKB1-deficient ILC3s had decreased survival, mitochondrial dysfunction, cytoplasmic lipid accumulation, and altered bioenergetics. Using LKB1 downstream kinase modulators, we found that LKB1 regulation of ILC3 survival and IL-22 production requires signaling through microtubule affinity-regulating kinases (MARKs). Mechanistically, LKB1 deficiency resulted in increased Reactive Oxygen Species (ROS) production and NFAT2 and PD-1 expression. Our work reveals that metabolic regulation of enteric ILC3 function by an LKB1-dependent signaling network is crucial for intestinal immunity and tissue homeostasis.

Keywords

CP: Immunology; CP: Metabolism; ILC3; LKB1; group 3 innate lymphoid cells; liver kinase B1; mitochondrial function.

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