Heme orchestrates a tissue stress response to proteolytic damage

Area of Science:

• Cellular Biology
• Physiology
• Pathology

Background:

• Cellular stress responses are well-understood, but tissue-level stress remains unclear.
• Excessive protease activity is linked to diseases like arthritis and COPD, but unifying stress features are unknown.

Purpose of the Study:

• To identify a conserved injury signature of proteolytic stress at the tissue level.
• To understand the sensing and adaptation mechanisms involved in tissue-level stress response.

Main Methods:

• Utilized lung tissue models with diverse proteases.
• Analyzed vascular disruption, red blood cell extravasation, and heme release.
• Investigated the roles of alveolar macrophages and fibroblasts in stress response.

Main Results:

• Identified a conserved proteolytic stress signature: vascular disruption, heme release, and subsequent oxidative stress.
• Alveolar macrophages act as primary sensors, activating NRF2-dependent heme detoxification.
• Fibroblasts produce protease inhibitors, limiting tissue damage.

Conclusions:

• Defined a unifying framework for tissue-level proteolytic stress sensing.
• Demonstrated that repeated proteolytic stress induces tissue adaptation and protection against injury and infection.