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Cell death in the gut epithelium and implications for chronic inflammation

Abstract

The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. As the transit-amplifying progenitors of the intestinal epithelium generate ~300 cells per crypt every day, regulated cell death and sloughing at the apical surface keeps the overall cell number in check. An aberrant increase in the rate of intestinal epithelial cell (IEC) death underlies instances of extensive epithelial erosion, which is characteristic of several intestinal diseases such as inflammatory bowel disease and infectious colitis. Emerging evidence points to a crucial role of necroptosis, autophagy and pyroptosis as important modes of programmed cell death in the intestine in addition to apoptosis. The mode of cell death affects tissue restitution responses and ultimately the long-term risks of intestinal fibrosis and colorectal cancer. A vicious cycle of intestinal barrier breach, misregulated cell death and subsequent inflammation is at the heart of chronic inflammatory and infectious gastrointestinal diseases. This Review discusses the underlying molecular and cellular underpinnings that control programmed cell death in IECs, which emerge during intestinal diseases. Translational aspects of cell death modulation for the development of novel therapeutic alternatives for inflammatory bowel diseases and colorectal cancer are also discussed.

Key points

  • During active flare-ups, various programmed cell death modes are elevated in the intestine of patients with inflammatory bowel disease, compromising the gut barrier.

  • Intestinal epithelial cells undergo programmed cell death through various modes including anoikis, apoptosis, necroptosis and pyroptosis.

  • Pyroptosis and necroptosis are pro-inflammatory, leading to the spread of inflammation, whereas anoikis and apoptosis restrict the spread of inflammation.

  • GSDMD and MLKL are two host proteins that execute pyroptosis and necroptosis, respectively, via the formation of membrane pores causing the leakage of intracellular contents and cell death.

  • Depending on the mode of cell death, factors derived from dead cells can trigger compensatory proliferation to replace the cells lost during inflammation.

  • There is an urgent need to characterize the proportion of various types of cell death that occur in different cellular compartments of the gut in patients with inflammatory bowel disease.

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Fig. 1: Common cell death programmes in the gut.
Fig. 2: Common molecular pathways of IEC death.
Fig. 3: Apoptosis and necroptosis of IECs and the related DAMPs.
Fig. 4: Intestinal cell death modes and DAMP clearance in inflammatory bowel disease.

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Acknowledgements

This work received funding from the DFG projects TRR241 (A03), SFB1181 (C05) and FOR2438 (TP05) and individual grant BE3686/9, as well as the Interdisciplinary Center for Clinical Research (IZKF; J68, A76).

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Glossary

Inflammasome

An oligomeric protein complex that is formed after various pattern recognition receptors are engaged and then binds to an adapter protein and pro-caspase 1, leading the maturation and activation of caspase 1 and pyroptotic cell death.

Caspase

A conserved family of cysteine-dependent aspartate-directed proteases that initiate and execute different molecular cell death pathways.

Apoptosome

A multimolecular protein complex with critical functions in apoptotic cell death; it is triggered by the release of cytochrome c from the mitochondria and consists of cytochrome c, apoptotic protease activating factor 1 and initiator caspases such as caspase 9.

Ripoptosome

A multiprotein complex that has a crucial role in the necroptotic form of cell death; it consists of receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 and forms when the TNF receptor is activated and the activity of the initiator caspase, caspase 8, is reduced or lacking.

Necrosis

A term that was used to describe non-programmed cell death due to chemical or mechanical damage; it is now restricted to describing cell death where all identifiable modes of programmed cell death have been ruled out or cannot be investigated and therefore the exact mode of cell death is unclear.

Oncosis

Also referred to as ischaemic cell death, oncosis is a process of cell death following cellular swelling involving disruption and swelling of intracellular organelles including the nucleus.

Anastasis

A mode of cellular ‘resurrection’ in which cells survive even after well-established molecular milestones of cell death have been reached, such as cytochrome c release and effector caspase activation.

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Patankar, J.V., Becker, C. Cell death in the gut epithelium and implications for chronic inflammation. Nat Rev Gastroenterol Hepatol 17, 543–556 (2020). https://doi.org/10.1038/s41575-020-0326-4

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