Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

WNT signalling shapes inflammatory responses in patients with sepsis (#56)

Johanna K Ljungberg 1 , Jessica C Kling 1 , Tien Dung Pham 2 , Kim-Anh Le Cao 2 , Melissa Lassig-Smith 3 , Cheryl Fourie 3 , Janine Stuart 3 , Therese Starr 3 , Jason Meyer 4 , Meg Harward 4 , Balasubramanian Venkatesh 4 5 6 7 8 , James Walsham 4 , Jeremy Cohen 5 6 8 9 , Antje Blumenthal 1 10
  1. University of Queensland, Diamantina Institute, Brisbane, QLD, Australia
  2. The University of Melbourne, Parkville, VIC, Australia
  3. Department of Intensive Care Medicine, Royal Brisbane and Women's hospital, Brisbane, QLD, Australia
  4. Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia
  5. The George Institute for Global Health, Sydney, NSW, Australia
  6. Wesley Hospital, Brisbane, QLD, Australia
  7. University of New South Wales, Sydney, NSW, Australia
  8. The University of Queensland, Brisbane, QLD, Australia
  9. Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
  10. Australian Infectious Diseases Centre, University of Queensland, Brisbane, QLD, Australia

Sepsis is a life-threatening condition characterised by uncontrolled systemic inflammation and subsequent organ dysfunction, resulting from a dysregulated host immune response to infection. Despite antibiotics and supportive therapies sepsis remains a leading cause of death globally, emphasising the need for novel treatment strategies. Molecular mechanisms that regulate immune responses to infection are being explored for opportunities for host-directed adjunct therapies in sepsis. The WNT signalling network has emerged as a regulator of inflammatory responses and dynamic WNT responses have been described in patients with sepsis and mouse models of severe infection. Key molecular bottle necks of WNT production and signalling have been identified as actionable drug targets and small molecule inhibitors have revealed that interference with WNT production and signalling curbed pro-inflammatory cytokine responses and prolonged host survival in mouse models of lipopolysaccharide-induced endotoxemia. Whether systemic inflammatory responses in patients with sepsis are sensitive to WNT inhibition is currently unknown. To address this, we recruited 45 patients admitted with sepsis to intensive care into the WiNTer study. Peripheral blood of each patient was cultured ex vivo in the presence of inhibitors of WNT production and signalling, and concentrations of pro- and anti-inflammatory cytokines, chemokines and growth factors determined. Inhibitors of WNT production significantly reduced the production of the majority of investigated analytes, and this was mirrored by inhibition of WNT/β-catenin signalling. The intimate connection between sepsis-associated inflammation and WNT responses was further confirmed by correlations analyses of gene expression in peripheral blood. Taken together, our data indicate that sepsis-associated inflammatory responses are underpinned by the activation of WNT/β-catenin signalling. This provides an essential step in the evaluation of the WNT signalling network as a target for therapeutic intervention in sepsis.