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Impact on the Sustainable Development Goals (SDGs)

Analysis of institutional authors

Delgado, M EugeniaCorresponding Author

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May 15, 2025
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Pharmacological LRH-1/Nr5a2 inhibition limits proinflammatory cytokine production in macrophages and associated experimental hepatitis

Publicated to: Cell Death & Disease. 11 (2): 154- - 2020-02-28 11(2), DOI: 10.1038/s41419-020-2348-9

Authors: Schwaderer, Juliane; Phan, Truong San; Gloeckner, Astrid; Delp, Johannes; Leist, Marcel; Brunner, Thomas; Delgado, M Eugenia

Affiliations

Univ Konstanz, Cooperat Doctorate Coll InViTe, Constance, Germany - Author
Univ Konstanz, Dept Biol, Biochem Pharmacol, Constance, Germany - Author
Univ Konstanz, Dept Biol, Vitro Toxicol & Biomed, Constance, Germany - Author
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Abstract

Liver receptor homolog-1 (LRH-1, Nr5a2) is an orphan nuclear receptor mainly expressed in tissues of endodermal origin, where its physiological role has been extensively studied. LRH-1 has been implicated in liver cell differentiation and proliferation, as well as glucose, lipid, and bile acid metabolism. In addition, increasing evidence highlights its role in immunoregulatory processes via glucocorticoid synthesis in the intestinal epithelium. Although the direct function of LRH-1 in immune cells is fairly elucidated, a role of LRH-1 in the regulation of macrophage differentiation has been recently reported. In this study, we aimed to investigate the role of LRH-1 in the regulation of pro-inflammatory cytokine production in macrophages. Our data demonstrate that pharmacological inhibition, along with LRH-1 knockdown, significantly reduced the lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines in the macrophage line RAW 264.7 cells, as well as in primary murine macrophages. This inhibitory effect was found to be independent of defects of LRH-1-regulated cell proliferation or toxic effects of the LRH-1 inhibitors. In contrast, LRH-1 inhibition reduced the mitochondrial ATP production and metabolism of macrophages through downregulation of the LRH-1 targets glucokinase and glutminase-2, and thus impairing the LPS-induced macrophage activation. Interestingly, in vivo pharmacological inhibition of LRH-1 also resulted in reduced tumor necrosis factor (TNF) production and associated decreased liver damage in a macrophage-and TNF-dependent mouse model of hepatitis. Noteworthy, despite hepatocytes expressing high levels of LRH-1, pharmacological inhibition of LRH-1 per se did not cause any obvious liver damage. Therefore, this study proposes LRH-1 as an emerging therapeutic target in the treatment of inflammatory disorders, especially where macrophages and cytokines critically decide the extent of inflammation.

Keywords

AnimalsCell differentiationCell proliferationCell-cycleCytokinesExpressionExtraadrenal glucocorticoid synthesisGenGene expressionGood health and well-beingGrowthHepatitisHepatocytesHomeostasisHomolog-1Intestinal mucosaLiver diseasesLiver receptorLrh-1MacrophagesMiceNr5a2 protein, mouseNuclear-receptorReceptors, cytoplasmic and nuclear

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Cell Death & Disease due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 37/195, thus managing to position itself as a Q1 (Primer Cuartil), in the category Cell Biology.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-12-10:

  • Open Alex: 24
  • WoS: 24
  • Scopus: 9
  • Europe PMC: 19

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-12-10:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 35.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 35 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 1.
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Continuing with the social impact of the work, it is important to emphasize that, due to its content, it can be assigned to the area of interest of ODS 3 - Good Health And Well-being, with a probability of 78% according to the mBERT algorithm developed by Aurora University.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (Delgado Martin, M. Eugenia).

the author responsible for correspondence tasks has been Delgado Martin, M. Eugenia.

Awards linked to the item

We thank Cindy Reinhold, Franziska Hartung, and Josefine Negrassus for expert technical help, and Kristina Schoonjans for the LRH-1 luciferase reporter constructs and the SHP-deficient mice. This work was supported by grants from the German Science Foundation (BR 3369/4-1, INST 38/500-1, INST 38/498-1) to T.B. and by an INNOSYSTOX (BMBF) grant to M.L. J.D. was supported by a Research and Art-funded Co-operative research training school "Advanced in vitro test systems for the analysis of cell-chemical interactions in drug discovery and environmental safety" (InViTe) fellowship from BadenWurttemberg Ministry of Science and MED by an Independent Research Grant from the Zukunftskolleg of the University of Konstanz.