Meprin and ADAM proteases as triggers of systemic inflammation in sepsis

Area of Science:

• Immunology
• Molecular Biology
• Pathology

Background:

• Systemic inflammatory disorders (SIDs) are characterized by excessive innate immune responses, leading to organ failure and death.
• Protease-mediated ectodomain shedding of cytokines and receptors is crucial for regulating inflammatory responses.
• A disintegrin and metalloproteinase (ADAM) 17 is a key sheddase for TNF-α and soluble IL-6 receptor, central to systemic inflammation.

Purpose of the Study:

• To review the role of ADAM10, ADAM17, and meprin metalloproteases in the onset and progression of sepsis.
• To discuss the therapeutic potential of these proteases in treating systemic inflammatory disorders.

Main Methods:

• Review of existing literature on ADAM proteases and meprins in systemic inflammation and sepsis models.
• Analysis of the mechanisms by which these proteases regulate cytokine shedding and inflammatory signaling.

Main Results:

• ADAM17 is a well-characterized sheddase releasing TNF-α and soluble IL-6 receptor, critical for inflammation.
• Meprin metalloproteases also shed IL-6 receptor and activate IL-1β and IL-18.
• Both ADAM17 and meprins were found to exacerbate disease progression in mouse models of sepsis.

Conclusions:

• ADAM10, ADAM17, and meprins play significant roles in the pathogenesis of sepsis.
• Targeting these proteases offers a promising therapeutic strategy for managing systemic inflammatory disorders and sepsis.