Reactive oxygen species stimulate Paneth cell plasticity and diminish antimicrobial function

Area of Science:

• Gastroenterology
• Immunology
• Cell Biology

Background:

• The gut epithelium is constantly exposed to oxidative stress.
• The role of reactive oxygen species (ROS) in Paneth cell (PC) response and function is not fully understood.

Purpose of the Study:

• To investigate how Paneth cells respond to oxidative stress and its implications for gut inflammation.
• To elucidate the role of CDC42 in regulating ROS, antimicrobial peptide production, and PC plasticity.

Main Methods:

• Utilized Paneth cell lineage reporters and genetic tracing.
• Employed gain- and loss-of-function approaches for CDC42.
• Assessed mitochondrial oxidative phosphorylation (OXPHOS) and ROS production.

Main Results:

• Elevated ROS induces Paneth cell division and dedifferentiation.
• Impaired mitochondrial respiration increases ROS, PC plasticity, and inflammation.
• CDC42 deficiency in PCs impairs mitochondrial respiration, elevates ROS, and promotes inflammation.

Conclusions:

• ROS directly suppress mature Paneth cell phenotypes, contributing to pathology in inflammatory diseases.
• Defects in OXPHOS balance and antimicrobial peptide production in PCs impair innate defense and drive intestinal inflammation.