Extracellular Neutrophil Proteases Are Efficient Regulators of IL-1, IL-33, and IL-36 Cytokine Activity but Poor Effectors of Microbial Killing

Abstract

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.

Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases

“…For instance, cleavage of TNF-a, IL-2, IL-6, the cytokine receptor chain IL-2R-a, or the IL-6R 80 kDa chain impairs their functionality. In contrast, cleavage of IL-8 by PR3 reportedly yielded a more active form of this chemokine (28), and NSPmediated processing increases the biologic activity of IL-1 family members (29,30).…”

Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis via activating keratinocytes

“…In turn, those migrated and infiltrated neutrophils also play a crucial role in amplifying the IL-36 autoinflammatory loop in psoriasis. Neutrophils, upon activation, release extracellular traps that contain several proteases including protease 3 or elastase, which can process and cleave IL-36 family to their biologically active forms (49)(50)(51).…”

Neutrophil Dynamics in Acute Coronary Syndrome

“…In patients with a history of myocardial infarction and elevated hs-CRP, canakinumab, targeting IL-1, represented another drug effective at preventing adverse cardiac events 3 . Serine proteases liberated from activated neutrophils, e.g., cathepsin G, elastase, proteinase-3, are potent regulators of at least six IL-1 cytokine family members, including IL-1 35 . One might consider inhibiting these extracellular proteases since this strategy will not affect neutrophil antimicrobial capability 35 .…”