A tissue-scale strategy for sensing threats in barrier organs

Area of Science:

• Immunology
• Cell Biology
• Respiratory Medicine

Background:

• Barrier organs utilize a restricted set of pattern recognition receptors (PRRs) to detect various immune challenges.
• Understanding how these organs balance host protection with collateral damage during immune responses is crucial.

Purpose of the Study:

• To investigate cell-type-specific threat sensing probabilities in the lung.
• To elucidate the mechanisms underlying differential immune responses across lung tissue compartments.

Main Methods:

• Single-molecule imaging to quantify infection detection probabilities.
• Spatial transcriptomics to map PRR expression across lung tissue.
• In vivo manipulation of retinoic acid-inducible gene I (RIG-I) levels in lung epithelia.

Main Results:

• Identified cell-type-specific threat sensing probabilities, with lower detection in epithelia and higher detection in the stroma.
• Demonstrated that spatially graded expression of nucleic acid-sensing PRRs drives these differential probabilities.
• Showed that increased RIG-I in lung epithelia exacerbates tissue damage during non-infectious challenges.

Conclusions:

• The lung employs a spatially tiered immune sensing strategy to manage threats.
• This strategy allows for tolerance of epithelia-restricted threats while enabling potent responses to deeper tissue invasions.
• Dampening epithelial sensitivity is vital for preventing excessive tissue damage.