Sonic hedgehog signalling in different forms of adrenal hyperplasia

• Antragstellerinnen: Privatdozentin Dr. Vasileia Ismini Alexaki; Professorin Dr. Suzanne Eaton (†)
• Fachliche Zuordnung: Endokrinologie, Diabetologie, Metabolismus
• Förderung: Förderung von 2011 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 189897882

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

We discovered that Shh produced by both adrenal and adrenocortical cancer cells consistents of a membrane associated pool, and a pool that is released on lipoprotein particles. We showed that the lipoprotein-associated Shh pool made by adrenocortical cancer cells cannot signal in either canonical and non-canonical assays because these cells also produce a lipophilic inhibitor that blocks signaling at the level or downstream of Smoothened. It will be fascinating, and of potential clinical importance, to identify this inhibitor. While the Shh form released by adrenocortical cancer cells does not signal, the cell-associated form signals canonically to adjacent fibroblasts. Addition of lipoproteins promotes release of Shh from cell membranes and the reduces ability of adrenocortical cells to signal in co-culture experiments. Although adrenocortical cancer cells can signal to adjacent cells, they cannot themselves respond to the Shh ligands they produce. Although they express Hh signaling pathway components, they lack primary cilia, which are critical for canonical Hh signaling. A similar situation may exist in the adrenal gland, where Shh produced by subcapsular cells signals canonically only to the adjacent capsule and not to cells in the cortex. We show that cortical cells produce Hh pathway components, but do not express Arl13b – a ciliary protein critical for pathway activation. In the future, it will be interesting to investigate whether the subcapsular Shh-expressing cells signaling to the capsule through direct contact, and whether this is inhibitable by lipoproteins. It will also be important to identifty the pathway inhibitor produced by NCI-H295R cells and ask whether this molecule affects Shh signaling in the adrenal. Overall, these findings suggest new mechanisms through which lipoproteins may affect Shh signaling in adrenal homeostasis. We also show that acute inflammation causes a metabolic shift in the adrenal cortex from TCA cycle and oxidative phosphorylation toward glycolysis and hypoxia. These metabolic changes are associated with oxidative stress and induction of apoptosis, as well as changes in Shh expression. The latter decreases in the first hours after application of LPS, while it fully recovers 24 hours post-treatment. We are currently trying to mechanistically explain these changes in Shh expression. We speculate that the Shh pathway might represent a novel player in recovery of homeostasis and resolution of inflammation in the adrenal gland after systemic inflammation.

Projektbezogene Publikationen (Auswahl)

• Lipoproteins and Hedgehog signalling - possible implications for the adrenal gland function. Eur J Clin Invest. 2013 Nov;43(11):1178-83
  Swierczynska MM, Lamounier-Zepter V, Bornstein SR, Eaton S
  
• Secretion and signaling activities of lipoprotein-associated hedgehog and non-sterol-modified hedgehog in flies and mammals. PLoS biology, 11(3), p.e1001505
  Palm W, Swierczynska MM, Kumari V, Ehrhart-Bornstein M, Bornstein SR, Eaton S
  
• Production of systemically circulating Hedgehog by the intestine couples nutrition to growth and development. Genes Dev. 2014 Dec 1;28(23):2636-51
  Rodenfels J, Lavrynenko O, Ayciriex S, Sampaio JL, Carvalho M, Shevchenko A, Eaton S
  
• Changes in morphology and function of adrenal cortex in mice fed a high-fat diet. Int J Obes (Lond). 2015 Feb;39(2):321-30
  Swierczynska MM, Mateska I, Peitzsch M, Bornstein SR, Chavakis T, Eisenhofer G, Lamounier- Zepter V, Eaton S
  
• Endocannabinoids are conserved inhibitors of the Hedgehog pathway. Proc Natl Acad Sci USA. 2015 Mar 17;112(11):3415-20
  Khaliullina H, Bilgin M, Sampaio JL, Shevchenko A, Eaton S
  
• Hedgehog signaling strength is orchestrated by the mir-310 cluster of microRNAs in response to diet. Genetics. 2016 Mar;202(3):1167-83
  Çiçek IÖ, Karaca S, Brankatschk M, Eaton S, Urlaub H, Shcherbata HR
  
• The role of innate immunity in the regulation of brown and beige adipogenesis. Rev Endocr Metab Disord. 2016 Mar;17(1):41-9
  Alexaki VI, Chavakis T
  
• S100A9 induces monocyte/ macrophage migration via EMMPRIN. Thromb Haemost. 2017 Feb 28;117(3):636-639
  Alexaki VI, May AE, Fujii C, V Ungern-Sternberg SN, Mund C, Gawaz M, Chavakis T, Seizer P
  
• DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB- Jmjd3 pathway. Mol Psychiatry. 2018 Jun;23(6):1410-1420
  Alexaki VI, Fodelianaki G, Neuwirth A, Mund C, Kourgiantaki A, Ieronimaki E, Lyroni K, Troullinaki M, Fujii C, Kanczkowski W, Ziogas A, Peitzsch M, Grossklaus S, Sönnichsen B, Gravanis A, Bornstein SR, Charalampopoulos I, Tsatsanis C, Chavakis T
  
• Nerve Growth Factor modulates LPS - induced microglial glycolysis and inflammatory responses. Exp Cell Res. 2019 Apr 15;377(1-2):10-16
  Fodelianaki G, Lansing F, Bhattarai P, Troullinaki M, Zeballos MA, Charalampopoulos I, Gravanis A, Mirtschink P, Chavakis T, Alexaki VI
  
• Nerve growth factor regulates endothelial cell survival and pathological retinal angiogenesis. J Cell Mol Med. 2019 Jan 24
  Troullinaki M, Alexaki VI, Mitroulis I, Witt A, Klotzsche-von Ameln A, Chung KJ, Chavakis T, Economopoulou M