WEHI Wednesday Seminar hosted by Professors James Murphy & James Vince

Dr Aysha Al-Ani
PhD Student – Murphy Laboratory, Inflammation division, WEHI

Jiyi Pang
PhD Student – Vince Laboratory, Inflammation division, WEHI
(this is a PhD Completion seminar)

A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic relapsing condition of the gastrointestinal tract that remains incurable. Approximately 180,000 Australians have IBD, with Australia estimated to have the highest incidence rate globally. Excessive intestinal epithelial cell death is implicated in IBD pathophysiology, however, the mechanisms and roles of programmed cell death in human IBD are poorly understood. This seminar will explore our findings based on the largest human cohort study of cell death in IBD, co-presented by Aysha Al-Ani and Jiyi Pang in two parts.

In the first part, Aysha will explore the role of necroptosis, a lytic programmed cell death pathway in IBD. Although cell death is not a recognised histologic feature of IBD, necroptotic signalling is increased in both CD and UC. Remarkably, this appears to arise in nascent inflammation, increasing with inflammatory burden regardless of treatment class and in a RIPK1-independent manner, challenging current dogma. Apoptotic signaling otherwise dominated inflamed regions, suggesting a necroptotic-to-apoptotic axis underlying disease activity. Gene set enrichment and bulk RNA sequencing confirmed interferon-gamma (IFNγ) and tumor necrosis factor (TNF)-related pathways linked to cell death signaling, and recapitulation of IBD inflammatory state in cytokine-treated epithelial organoid assays.

In the second part of this seminar, Jiyi will subsequently explore the mechanistic regulation of cytokinedriven epithelial cell death using human intestinal organoid models. We found that IFNγ stimulation upregulated genes involved in apoptotic and necroptotic cell death pathways. Co-treatment with IFNγ and TNF amplified cell death gene signatures, leading to extensive intestinal organoid killing. Mechanistically, IFNγ and TNF triggers inducible nitric oxide synthetase (iNOS)-dependent and iNOS-independent cell death mechanisms across different intestinal cell types, which also involves BCL-2 family proteins.

Together, our findings reveal persistent dysregulated cell death in IBD despite histological remission using advanced medical therapies. A unique mechanistic framework of inflammation-driven intestinal epithelial cell death is unveiled, suggesting targeting the necroptotic to-apoptotic axis is a potential prognostic and therapeutic strategy for achieving deep and sustained remission. 

All welcome!