Meprin and ADAM proteases as triggers of systemic inflammation in sepsis.

ABSTRACT

Systemic inflammatory disorders (SIDs) comprise a broad range of diseases characterized by dysregulated excessive innate immune responses. Severe forms of SIDs can lead to organ failure and death, and their increasing incidence represents a major issue for the healthcare system. Protease-mediated ectodomain shedding of cytokines and their receptors represents a central mechanism in the regulation of inflammatory responses. The metalloprotease A disintegrin and metalloproteinase (ADAM) 17 is the best-characterized ectodomain sheddase capable of releasing TNF-α and soluble IL-6 receptor, which are decisive factors of systemic inflammation. Recently, meprin metalloproteases were also identified as IL-6 receptor sheddases and activators of the pro-inflammatory cytokines IL-1ß and IL-18. In different mouse models of SID, particularly those mimicking a sepsis-like phenotype, ADAM17 and meprins have been found to promote disease progression. In this review, we summarize the role of ADAM10, ADAM17, and meprins in the onset and progression of sepsis and discuss their potential as therapeutic targets.