Role of Interleukin-17 during Acute Lung Injury and Septic Shock in vivo

• Applicant: Professor Dr. Markus Bosmann
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2009 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 157542375

• Final Report Year: 2012

Final Report Abstract

Septic Shock and Acute Lung Injury are leading causes of morbidity and mortality in critical care medicine confronting clinicians with the non-availability of specific treatment strategies. During the completed project the implications of IL-17 and related mediators during the pathogenesis of Septic Shock and Acute Lung Injury were investigated. The concentrations of IL-17A were elevated during experimental models of Acute Lung Injury, Septic Shock and polymicrobial Sepsis after cecal ligation and puncture. Neutralisation of IL-17A during Septic Shock improved survival rates of C57BL/6J mice. Major cellular sources of IL-17A appeared to be not only lymphocytes but also included macrophages. The role of the complement activation product, C5a, was studied during Acute Lung Injury, Septic Shock and in cultures of macrophages. C5a suppressed the release of IL-17A from macrophages and at the same time amplified production of the less potent isofomi IL-17F. Mechanistically, C5a activated PI3K/Akt, MEK1/2 and ERK1/2 kinase pathways to induce IL-10 which subsequently suppressed IL-17A in an autocrine/paracrine fashion. These studies have provided novel insights into the molecular mechanisms underlying the development and progression of Acute Lung Injury and Septic Shock.

Publications

• (2011). Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis. FASEB Journal. Dec 27. [Epub ahead of print]
  Bosmann M., Sarma J. V., Atefi G., Zetoune F. S., Ward P. A.
  
• (2011). MyD88-dependent production of IL-17F is modulated by the anaphylatoxin C5a: Role of the Akt signaling pathway. FASEB Journal Dec;25(12):4222-32. Epub 2011 Aug 22
  Bosmann M., Patel V. R., Russkamp N. F., Pache F., Zetoune F. S., Sarma J. V., Ward P. A.
  
• (2011). The outcome of polymicrobial sepsis is independent of T and B cells. Shock. Oct;36(4):396-401
  Bosmann M., Russkamp N. F., Patel V. R., Zetoune F. S., Sarma J. V., Ward P. A.
  
• (2012) Anti-inflammatory Effects of β2 Adrenergic Receptor Agonists in Experimental Acute Lung Injury. FASEB Journal. Feb 7. [Epub ahead of print]
  Bosmann M., Zhu K., Grailer J. J., Matthay M. A., Samia J. V., Zetoune F. S., Ward P. A.