Dissecting the adrenal-endothelial-immune interface in systemic inflammation: Implications for inflammationrelated adrenal dysfunction
Final Report Abstract
Systemic inflammation and adrenal gland function are intimately linked in a bidirectional fashion. Adrenal gland function and adrenal hormones modulate systemic inflammation. Adrenal dysregulation and an inadequate steroid response, often observed in the course of systemic inflammation, may therefore negatively affect the outcome of systemic inflammation. In this regard, immune cells that accumulate in the adrenal gland in the course of inflammation, and the products thereof, especially pro-inflammatory cytokines, may contribute to adrenal dysfunction. As the adrenal gland is highly vascularized, endothelial cells are a critical intermediate of the aforementioned immune-adrenal crosstalk in systemic inflammation. On the other hand, leukocyte interactions with the endothelium are an important component of the systemic inflammatory response; leukocyte-endothelial interactions may in turn be regulated by adrenal steroids. The present project focused on the understanding of this complex adrenal-endothelial-immune interface in the course of systemic inflammation. In this regard, we could demonstrate that the endogenous anti-inflammatory factor, endothelial-derived Del-1 (Developmental endothelial locus 1), which interacts with integrins and antagonizes leukocyte adhesive events, acts as a gatekeeper of adrenal gland inflammation. In the course of systemic inflammation, downregulation of Del-1 expression in the adrenal gland promoted adrenal gland inflammation and adrenal dysfunction. To our knowledge, these findings represent likely the first study demonstrating the important role of the adrenal endothelium in supporting adrenal homeostasis and counter-acting inflammation-related adrenal dysfunction. Moreover, we have provided mechanistic insights into the adrenal-endothelial-immune interface in systemic inflammation, by investigating a complex regulatory loop, in which the endothelium and endothelial Del-1 expression lie in the centre. We identified the molecular mechanisms, by which pro-inflammatory cytokines, such as IL-17, inhibit endothelial Del-1 expression. Importantly, we also identified molecular mechanisms potentially explaining the anti-inflammatory actions of the adrenal steroid dehydroepiandrosterone (DHEA) (its immunomodulatory functions are known for long time but not well understood mechanistically). These mechanisms involved DHEA-induced signalling via its receptor TRKA and modulation of Del-1 expression. Hence, our studies have led to a much better understanding of the molecular mechanisms underlying the anti-inflammatory effects of the aforementioned adrenal steroid. Together, the present project revealed important mechanisms underlying the adrenal-endothelial-immune interface in systemic inflammation and provides molecular targets for potential therapeutic interventions for inflammation-related adrenal dysfunction.
Publications
- Hypothalamo-pituitary and immunedependent adrenal regulation during systemic inflammation. Proc Natl Acad Sci USA. 2013; 110:14801-6
Kanczkowski W, Alexaki VI, Tran N, Großklaus S, Zacharowski K, Martinez A, Popovics P, Block NL, Chavakis T, Schally AV, Bornstein SR
(See online at https://doi.org/10.1073/pnas.1313945110) - Role of the endothelial-derived endogenous anti-inflammatory factor Del-1 in inflammation-mediated adrenal gland dysfunction. Endocrinology. 2013; 154:1181-9
Kanczkowski W, Chatzigeorgiou A, Grossklaus S, Sprott D, Bornstein SR, Chavakis T
(See online at https://doi.org/10.1210/en.2012-1617) - Blocking CD40- TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proc Natl Acad Sci USA. 2014; 111:2686-91
Chatzigeorgiou A, Seijkens T, Zarzycka B, Engel D, Poggi M, van den Berg S, van den Berg S, Soehnlein O, Winkels H, Beckers L, Lievens D, Driessen A, Kusters P, Biessen E, Garcia-Martin R, Klotzsche-von Ameln A, Gijbels M, Noelle R, Boon L, Hackeng T, Schulte KM, Xu A, Vriend G, Nabuurs S, Chung KJ, Willems van Dijk K, Rensen PC, Gerdes N, de Winther M, Block NL, Schally AV, Weber C, Bornstein SR, Nicolaes G, Chavakis T, Lutgens E
(See online at https://doi.org/10.1073/pnas.1400419111) - Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X. Int J Cancer. 2014; 135:2054-64
Qin N, de Cubas AA, Garcia-Martin R, Richter S, Peitzsch M, Menschikowski M, Lenders JW, Timmers HJ, Mannelli M, Opocher G, Economopoulou M, Siegert G, Chavakis T, Pacak K, Robledo M, Eisenhofer G
(See online at https://doi.org/10.1002/ijc.28868) - Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway. Nat Commun. 2015 Sep 16; 6:8272
Maekawa T, Hosur K, Abe T, Kantarci A, Ziogas A, Wang B, Van Dyke TE, Chavakis T, Hajishengallis G
(See online at https://doi.org/10.1038/ncomms9272) - Changes in morphology and function of adrenal cortex in mice fed a high-fat diet. Int J Obes (Lond). 2015; 39:321-30
Swierczynska MM, Mateska I, Peitzsch M, Bornstein SR, Chavakis T, Eisenhofer G, Lamounier-Zepter V, Eaton S
(See online at https://doi.org/10.1038/ijo.2014.102) - Multipotent glia-like stem cells mediate stress adaptation. Stem Cells. 2015; 33:2037-51
Rubin de Celis MF, Garcia-Martin R, Wittig D, Valencia GD, Enikolopov G, Funk RH, Chavakis T, Bornstein SR, Androutsellis-Theotokis A, Ehrhart-Bornstein M
(See online at https://doi.org/10.1002/stem.2002) - Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation. Mol Cell Biol. 2016; 36:376-93
García-Martín R, Alexaki VI, Qin N, Rubín de Celis MF, Economopoulou M, Ziogas A, Gercken B, Kotlabova K, Phieler J, Ehrhart-Bornstein M, Bornstein SR, Eisenhofer G, Breier G, Blüher M, Hampe J, El-Armouche A, Chatzigeorgiou A, Chung KJ, Chavakis T
(See online at https://doi.org/10.1128/MCB.00430-15) - From leukocyte recruitment to resolution of inflammation: the cardinal role of integrins. J Leukoc Biol. 2017; 102:677-683
Kourtzelis I, Mitroulis I, von Renesse J, Hajishengallis G, Chavakis T
(See online at https://doi.org/10.1189/jlb.3MR0117-024R) - DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway. Mol Psychiatry. 2018; 23:1410-1420
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
(See online at https://doi.org/10.1038/mp.2017.167) - DEL-1-Regulated Immune Plasticity and Inflammatory Disorders. Trends Mol Med. 2019; 25:444-459
Hajishengallis G, Chavakis T
(See online at https://doi.org/10.1016/j.molmed.2019.02.010) - Endothelial-Specific Deficiency of ATG5 (Autophagy Protein 5) Attenuates Ischemia-Related Angiogenesis. Arterioscler Thromb Vasc Biol. 2019; 39:1137-48
Sprott D, Poitz DM, Korovina I, Ziogas A, Phieler J, Chatzigeorgiou A, Mitroulis I, Deussen A, Chavakis T, Klotzsche-von Ameln A
(See online at https://doi.org/10.1161/ATVBAHA.119.309973)
