Extracellular neutrophil proteases are efficient regulators of IL-1, IL-33, and IL-36 cytokine activity but poor effectors of microbial killing

Neutrophil granule proteases are thought to function as anti-microbial effectors, cooperatively hydrolyzing microorganisms within phagosomes, or upon deployment into the extracellular space. However, evidence also suggests that neutrophil proteases play an important role in the coordination and escalation of inflammatory reactions, but how this is achieved has been obscure. IL-1 family cytokines are important initiators of inflammation and are typically released via necrosis but require proteolytic processing for activation. Here, we show that proteases liberated from activated neutrophils can positively or negatively regulate the activity of six IL-1 family cytokines (IL-1α IL-1β IL-33, IL-36α IL-36β and IL-36γ) with exquisite sensitivity. In contrast, extracellular neutrophil proteases displayed very poor bactericidal activity, exhibiting 100-fold greater potency toward cytokine processing than bacterial killing. Thus, in addition to their classical role as phagocytes, neutrophils play an important immunoregulatory role through deployment of their granule proteases into the extracellular space to process multiple IL-1 family cytokines. Here, Clancy et al. show that proteases released by activated neutrophils into the extracellular space exhibited poor antimicrobial activity but were potent modulators of IL-1α IL-1β IL-33, IL-36α IL-36β and IL-36γ activation states. Thus, neutrophils play a key role in modulating inflammatory responses through processing of multiple IL-1 family cytokines.