Alarmins: Feel the Stress.

Area of Science:

• Immunology
• Cellular Biology
• Molecular Medicine

Background:

• Danger-associated molecular pattern molecules (alarmins) are known mediators of sterile inflammation following trauma.
• The 'danger hypothesis' traditionally proposed passive release of alarmins from damaged cells.
• Recent findings indicate alarmins can be released from live cells under physiological stress, signaling damage without cell lysis.

Purpose of the Study:

• To review the role of specific alarmins (IL-1α, IL-33, IL-16, HMGB1) in cellular and physiological stress.
• To propose a novel function of these molecules as 'stressorins' that initiate sterile inflammation in response to nonlethal stress.
• To highlight the significance of posttranslational modifications in regulating stressorin activity.

Main Methods:

• Review of existing literature on alarmins, sterile inflammation, and cellular stress.
• Analysis of signaling mechanisms involved in alarmin release from stressed, non-lysed cells.
• Discussion of posttranslational modifications affecting alarmin function.

Main Results:

• Alarmins can be actively released from live cells experiencing physiological stress, independent of cell death.
• These released alarmins act as initiators of sterile inflammation, termed 'stressorins'.
• Posttranslational modifications are critical regulators of stressorin activity and inflammatory signaling.

Conclusions:

• Alarmins function not only passively but also actively as 'stressorins' in initiating sterile inflammation.
• Targeting stressorins or their modifying enzymes presents a novel therapeutic strategy for inflammatory diseases.
• This revised understanding opens new avenues for developing anti-inflammatory treatments.