Interferon regulatory factor 6 (IRF6) determines intestinal epithelial cell development and immunity.

Area of Science:

• Immunology
• Cell Biology
• Gastroenterology

Background:

• Intestinal epithelial cells (IECs) mount antiviral defenses via interferon (IFN) signaling, but the regulatory factors are unclear.
• Interferon regulatory factors (IRFs) are key transcription factors; IRF6 is abundant in epithelial cells, yet its immune function in the gut is unknown.

Purpose of the Study:

• To investigate the role of IRF6 in regulating intestinal epithelial cell immunity and homeostasis.
• To determine how IRF6 deficiency impacts epithelial cell responses to interferon and inflammasome activation.

Main Methods:

• Utilized Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screening in mouse IECs.
• Generated and analyzed Irf6 knockout (KO) mouse IEC organoids using single-cell RNA sequencing.
• Assessed organoid growth, gene expression, and cytotoxicity following IFN or inflammasome stimulation.

Main Results:

• Irf6 deficiency enhanced IFN-stimulated antiviral responses in transformed IECs.
• Irf6 KO organoids exhibited impaired homeostasis, reduced epithelial differentiation, and altered immune gene expression.
• Loss of IRF6 led to increased stress, apoptosis, and cytotoxicity in IECs upon IFN or inflammasome activation.

Conclusions:

• IRF6 plays a critical role in maintaining intestinal epithelial cell homeostasis and regulating innate immune responses.
• IRF6 acts to minimize cytotoxicity during immune activation, thereby preserving intestinal barrier function.
• This study reveals a novel function for IRF6 in moderating epithelial immunity.