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Harnessing Distinct Tissue-Resident Immune Niches via S100A9/TLR4 Improves Ketone, Lipid, and Glucose Metabolism

Lucibello, Giulia ; Ursino, Gloria ; Teixeira, Pryscila D.S. ; Zahoran, Szabolcs ; Fanuele, Francesca ; Kallikourdis, Marinos ; Visentin, Florian ; Veyrat-Durebex, Christelle ; Widmer, Ariane and Wu, Yibo , et al. (2025) In Endocrinology (United States) 166(10).
Abstract

The importance of immunometabolism in the development of metabolic diseases is clear. Yet, how certain metabolic disorders, such as insulin deficiency (ID), influence immune cell function, and vice versa, is poorly understood. Also, therapeutic strategies to harness the interplay between immune cells and metabolism are lacking. Here, we observe that ID rearranges the immune landscape of the liver, causing a decrease of T cells and an increase of the Kupffer cells, accompanied by a shift in the transcriptional signature and polarization of the latter. Treating ID mice with the protein S100A9 rescues the polarization and lipid-related changes caused by ID in the Kupffer cells, and, through them, rescues hypertriglyceridemia and... (More)

The importance of immunometabolism in the development of metabolic diseases is clear. Yet, how certain metabolic disorders, such as insulin deficiency (ID), influence immune cell function, and vice versa, is poorly understood. Also, therapeutic strategies to harness the interplay between immune cells and metabolism are lacking. Here, we observe that ID rearranges the immune landscape of the liver, causing a decrease of T cells and an increase of the Kupffer cells, accompanied by a shift in the transcriptional signature and polarization of the latter. Treating ID mice with the protein S100A9 rescues the polarization and lipid-related changes caused by ID in the Kupffer cells, and, through them, rescues hypertriglyceridemia and hyperketonemia in a TLR4-dependent manner. Additionally, S100A9 acts on other immune niches to increase glucose uptake in skeletal muscle, improving hyperglycemia. In summary, our findings pinpoint the S100A9-TLR4 axis as a new tool to harness immune cells for improving ID-related metabolic dysfunction.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
diabetes, immunometabolism, Kupffer cell, S100A9, skeletal muscle, TLR4
in
Endocrinology (United States)
volume
166
issue
10
article number
bqaf131
publisher
Endocrine Society
external identifiers
  • scopus:105015354892
  • pmid:40874857
ISSN
0013-7227
DOI
10.1210/endocr/bqaf131
language
English
LU publication?
yes
id
9de9d775-cbf3-4f9d-bc64-47dfef6d7d29
date added to LUP
2025-10-10 13:00:30
date last changed
2025-10-11 03:00:08
@article{9de9d775-cbf3-4f9d-bc64-47dfef6d7d29,
  abstract     = {{<p>The importance of immunometabolism in the development of metabolic diseases is clear. Yet, how certain metabolic disorders, such as insulin deficiency (ID), influence immune cell function, and vice versa, is poorly understood. Also, therapeutic strategies to harness the interplay between immune cells and metabolism are lacking. Here, we observe that ID rearranges the immune landscape of the liver, causing a decrease of T cells and an increase of the Kupffer cells, accompanied by a shift in the transcriptional signature and polarization of the latter. Treating ID mice with the protein S100A9 rescues the polarization and lipid-related changes caused by ID in the Kupffer cells, and, through them, rescues hypertriglyceridemia and hyperketonemia in a TLR4-dependent manner. Additionally, S100A9 acts on other immune niches to increase glucose uptake in skeletal muscle, improving hyperglycemia. In summary, our findings pinpoint the S100A9-TLR4 axis as a new tool to harness immune cells for improving ID-related metabolic dysfunction.</p>}},
  author       = {{Lucibello, Giulia and Ursino, Gloria and Teixeira, Pryscila D.S. and Zahoran, Szabolcs and Fanuele, Francesca and Kallikourdis, Marinos and Visentin, Florian and Veyrat-Durebex, Christelle and Widmer, Ariane and Wu, Yibo and Cremonesi, Marco and Wollheim, Claes B. and Castets, Perrine and Ramadori, Giorgio and Coppari, Roberto}},
  issn         = {{0013-7227}},
  keywords     = {{diabetes; immunometabolism; Kupffer cell; S100A9; skeletal muscle; TLR4}},
  language     = {{eng}},
  number       = {{10}},
  publisher    = {{Endocrine Society}},
  series       = {{Endocrinology (United States)}},
  title        = {{Harnessing Distinct Tissue-Resident Immune Niches via S100A9/TLR4 Improves Ketone, Lipid, and Glucose Metabolism}},
  url          = {{http://dx.doi.org/10.1210/endocr/bqaf131}},
  doi          = {{10.1210/endocr/bqaf131}},
  volume       = {{166}},
  year         = {{2025}},
}