Immune mechanisms and potential therapeutic interventions for sepsis-induced adrenal gland inflammation

• Antragsteller: Professor Dr. Stefan R. Bornstein; Dr. Waldemar Kanczkowski; Professor Kai Zacharowski, Ph.D.
• Fachliche Zuordnung: Endokrinologie, Diabetologie, Metabolismus
• Förderung: Förderung von 2011 bis 2018
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 189897882

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

Activation of the adrenal gland stress response is of utmost importance to survive sepsis. Experimental and clinical evidence exists demonstrating that adrenal gland often develops functional and structural damage due to sepsis with mechanisms remaining largely unknown. The main aim of the Project 7, within the KFO 252/2, was to establish and to characterize a clinically experimental model to study adrenal gland dysregulation, and to explore the potential mechanisms that could contribute to adrenal insufficiency. During both funding periods, we have successfully characterised the adrenal gland function and dysfunction during LPS – induced SIRS and a cecal-ligation and puncture (CLP)-mediated sepsis. Our results revealed that CLP-OP mimics more closely a clinical situation. In particular, we have found that mortality of mice due to CLP-induced sepsis positively correlated with various features of adrenal dysfunction including, elevated intra-adrenal inflammation, infiltration of immune cells, bleeding, cell death and blunted corticosterone response to exogenous ACTH (a current test used for indication of adrenal insufficiency). In order to find the mechanisms involved in adrenal dysfunction, we have comprehensively analysed the adrenal gland microenvironment, including resident and recruited immune cells, dysfunction of adrenal vascular cells, as well as the key role of hematopoietic TLR-signalling in control of adrenal inflammation during sepsis. In particular, we have identified the myeloid and liver- but not adrenocortical cell counterpart of adrenal gland microenvironment, as being crucially involved in hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal inflammation. However, further validation of those results in mice with hematopoietic – specific inactivation of TLR signalling revealed that although immune TLR-signalling drives systemic and adrenal gland inflammation, it does not solely control activation of the HPA axis. Surprisingly, we have found that instead, it was required for proper adrenomedullary stress response (epinephrine secretion). Based on that knowledge, we are now currently investigating the protective role of multiple therapeutic agents including inhibitors of C5aR (PMX53 and avocapan). We also plan in the near future to test our experience gained within this KFO 252 in humanized mouse models of sepsis, which approach, as we hope, will allow us to shift our research into clinical trials. The recent RNA-seq analysis of the global changes in the adrenal gland transcriptome upon LPS provided us also with multiple new and highly interesting directions, in particular, adrenal regeneration and hypoxia pathways, of which we plan additionally to explore in future.

Projektbezogene Publikationen (Auswahl)

• Endothelial dysfunction: a critical determinant in inflammation-associated adrenal insufficiency? Eur J Clin Invest. 2011;41(8):917-9
  Chavakis T, Kanczkowski W, Willenberg HS, Bornstein SR
  
• Isolation, characterization, and differentiation of progenitor cells from human adult adrenal medulla. Stem Cells Transl Med. 2012;1(11):783-91
  Santana MM, Chung KF, Vukicevic V, Rosmaninho-Salgado J, Kanczkowski W, Cortez V, Hackmann K, Bastos CA, Mota A, Schrock E, Bornstein SR, Cavadas C, Ehrhart-Bornstein M
  
• Characterization of the LPS-induced inflammation of the adrenal gland in mice. Mol Cell Endocrinol. 2013;371(1-2):228-35
  Kanczkowski W, Chatzigeorgiou A, Samus M, Tran N, Zacharowski K, Chavakis T, Bornstein SR
  
• Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation. Proc Natl Acad Sci USA. 2013;110(36):14801-6
  Kanczkowski W, Alexaki VI, Tran N, Großklaus S, Zacharowski K, Martinez A, Popovics P, Block NL, Chavakis T, Schally AV, Bornstein SR
  
• Role of the endothelial-derived endogenous anti-inflammatory factor Del-1 in inflammationmediated adrenal gland dysfunction. Endocrinology. 2013;154:1181-9
  Kanczkowski W, Chatzigeorgiou A, Grossklaus S, Sprott D, Bornstein SR, Chavakis T
  
• Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormonereleasing hormone. Proc Natl Acad Sci USA. 2013;110(6):2288-93
  Schubert U, Schmid J, Lehmann S, Zhang XY, Morawietz H, Block NL, Kanczkowski W, Schally AV, Bornstein SR, Ludwig B
  
• Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology. 2014;60(4):1196-210
  Chatzigeorgiou A, Chung KJ, Garcia-Martin R, Alexaki VI, Klotzsche-von Ameln A, Phieler J, Sprott D, Kanczkowski W, Tzanavari T, Bdeir M, Bergmann S, Cartellieri M, Bachmann M, Nikolakopoulou P, Androutsellis-Theotokis A, Siegert G, Bornstein SR, Muders MH, Boon L, Karalis KP, Lutgens E, Chavakis T
  
• New insights into the controversy of adrenal function during critical illness. Lancet Diabetes Endocrinol. 2015;3(10):805-15
  Boonen E, Bornstein SR, Van den Berghe G
  
• The role of adrenal gland microenvironment in the HPA axis function and dysfunction during sepsis. Mol Cell Endocrinol. 2015;408:241-8
  Kanczkowski W, Sue M, Zacharowski K, Reincke M, Bornstein SR
  
• Adrenal gland microenvironment and its involvement in the regulation of stress-induced hormone secretion during sepsis. Front Endocrinol (Lausanne). 2016;7:156
  Kanczkowski W, Sue M, Bornstein SR
  
• Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-89
  Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ
  
• Mortality of septic mice strongly correlates with adrenal gland inflammation. Crit Care Med. 2016;44(4):e190-9
  Jennewein C, Tran N, Kanczkowski W, Heerdegen L, Kantharajah A, Dröse S, Bornstein S, Scheller B, Zacharowski K
  
• RNA-seq analysis of LPS-induced transcriptional changes and its possible implications for the adrenal gland dysregulation during sepsis. J. Steroid Biochem. Mol. Biol. 2019;191:105360
  Chen LS, Singh SP, Schuster M, Grinenko T, Bornstein SR, Kanczkowski W