CXCL8 greatly enhances neutrophil extracellular traps formation induced by calcium crystals in vitro and in vivo

Neutrophil extracellular traps (NETs) contribute to host defense but can also drive sterile inflammation and tissue injury. Among particulate inducers, monosodium urate and calcium crystals are potent triggers of NETosis. The role of the chemokine interleukin-8 (CXCL8) in NET formation, however, has remained controversial and context-dependent. Here we show that CXCL8 markedly amplifies NETosis induced by calcium carbonate (CaCO3) and calcium pyrophosphate dihydrate (CPPD) crystals in human neutrophils. This cooperative effect was independent of crystal composition, required cytoskeletal rearrangements, and was abrogated by inhibition of Src family kinases, PI3K, or ERK1/2, but not by blockade of NADPH oxidase. In a murine model, combined administration of CXCL8 and CaCO3 crystals significantly increased serum citrullinated histone H3 compared with crystals alone, confirming the potentiating effect in vivo. These findings identify an unrecognized crosstalk between chemokine signaling and crystal-driven NETosis, providing mechanistic insight into sterile inflammatory diseases including gout, pseudogout, atherosclerosis, and pancreatitis, and supporting the concept that antagonists of CXCL8 receptors (CXCR1/2) could limit pathological NET formation.