The intestinal mucosa is continuously exposed to bacteria and dietary components. Immune and non-immune cells within the mucosal tissue can detect pathogenic molecules and microorganisms and initiate protective responses. Both these immune reactions and pathogenic factors can lead to tissue damage.
Under normal conditions, the immune system and intestinal epithelial cells maintain a balance: they protect tissue from injury while simultaneously promoting repair. In inflammatory bowel diseases (IBD) – such as Crohn’s disease and ulcerative colitis – this balance is disrupted. Chronic inflammation develops in the intestine, and damaged mucosal tissue heals poorly.
An international team of researchers reviewed current knowledge regarding the role of interferon lambda (IFN-λ, type III interferon) in intestinal repair. Previous studies suggested that IFN-λ may reduce inflammation and support mucosal integrity. However, other studies indicated that excessive IFN-λ expression can induce the death of epithelial cells and Paneth cells, which support intestinal epithelial regeneration. Furthermore, patients with IBD exhibit elevated levels of IFN-λ and its receptor. Nevertheless, it has remained unclear whether these changes are protective or harmful.
IFN-λ Delays Tissue Repair After Injury
During recovery from colitis or radiation-induced injury, IFN-III signaling – but not IFN-I signaling – in intestinal epithelial cells slows tissue regeneration.
Elevated IFN-λ activity persists in the intestine during both active colitis and remission. Mice whose intestinal epithelial cells were unable to respond to IFN-λ signals showed faster restoration of colon length, epithelial integrity, and body weight after colitis. In contrast, administration of IFN-λ delayed healing. A similar effect was observed following radiation-induced intestinal injury: loss of the IFN-λ receptor promoted tissue regeneration and improved survival, whereas administration of IFN-λ impaired recovery and increased mortality.
These effects were specifically associated with IFN-λ action on intestinal epithelial cells rather than on neutrophils. Type I interferons did not affect regenerative processes.
IFN-λ Suppresses the Regenerative Program of the Intestinal Epithelium
Gene expression analysis showed that IFN-λ activates antiviral and antibacterial pathways in intestinal epithelial cells while simultaneously suppressing genes involved in tissue regeneration, cell proliferation, and mucosal healing.
Mice lacking the IFN-λ receptor in the intestinal epithelium exhibited enhanced regenerative and proliferative programs, as well as increased numbers of intestinal stem cells responsible for tissue repair after injury. In contrast, mice with intact IFN-λ signaling displayed a reduced stem cell pool and accumulation of immature progenitor cells within the tissue.
Thus, IFN-λ initiates a transcriptional program that restricts intestinal stem cell expansion and suppresses epithelial regeneration following injury.
IFN-λ Delays Intestinal Repair Through Activation of the ZBP1–Caspase-8–GSDMC Pathway
In epithelial cells, IFN-λ increases ZBP1 expression, a regulator of apoptosis, necroptosis, and pyroptosis, thereby triggering caspase-8 activation, which cleaves GSDMC family proteins. As a result, epithelial cells are destroyed through membrane damage, limiting epithelial regeneration.
Following colitis and radiation-induced injury, activation of the ZBP1–caspase-8–GSDMC pathway was observed only in mice whose epithelium remained responsive to IFN-λ. In the absence of the IFN-λ receptor, ZBP1, or GSDMC, or following pharmacological inhibition of caspase-8, this signaling cascade was not activated, and mucosal healing after inflammatory and radiation-induced injury occurred more rapidly.
Loss of GSDMC in intestinal epithelial cells promoted tissue recovery after colitis. Mice lacking GSDMC retained more epithelial cells and showed increased numbers of cells involved in epithelial regeneration.
IFN-λ Promotes Formation of a Multiprotein Complex That Detects Z-Nucleic Acids and Delays Intestinal Repair After Injury
Researchers found that IFN-λ alone is insufficient to induce intestinal epithelial cell death; an additional signal generated by tissue injury is required. This signal was identified as Z-nucleic acids, whose levels increased following colitis and radiation-induced damage.
The ZBP1 protein recognized Z-nucleic acids, promoted the formation of a signaling complex involving RIPK1 and caspases, activated caspase-8 and GSDMC, and triggered pyroptosis – an inflammatory form of cell death.
Deletion of the ZBP1 domain responsible for binding Z-nucleic acids reduced cell death and accelerated intestinal recovery.
The IFN-λ–ZBP1–Caspase-8–GSDMC Axis Is Active in Patients With IBD
Patients with inflammatory bowel disease showed elevated expression of ZBP1, CASP8, and GSDMC, particularly during active disease. At the same time, interferon responses, proinflammatory signaling pathways, and cell death pathways were enhanced.
Among IFN-λ family members, IFN-λ2 and IFN-λ3 were the most abundant in patients with IBD. Their levels correlated with levels of ZBP1, activated caspase-8, and cleaved GSDMC. Furthermore, the levels of ZBP1, caspase-8, and GSDMC were also strongly correlated with one another.
These findings indicate that IFN-λ is associated with activation of ZBP1, caspase-8, and GSDMC in patients with IBD.
Conclusion
IFN-λ delays intestinal recovery after inflammatory and radiation-induced injury by activating the ZBP1–caspase-8–GSDMC pathway in epithelial cells, which triggers pyroptosis. This mechanism was confirmed in both mice and patients with ulcerative colitis and Crohn’s disease.
IFN-λ induces cell death only under conditions of tissue damage, when Z-nucleic acids accumulate and provide the second signal required for ZBP1 activation. In the absence of tissue injury, this pathway remains inactive and does not affect normal intestinal epithelial turnover.
IFN-λ2 and IFN-λ3 are key factors limiting intestinal epithelial regeneration, making this signaling pathway a promising therapeutic target for inflammatory bowel disease and radiation-induced intestinal injury.
Reference
Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair
