FIGURE 4.

Netosis is initiated by activation of neutrophils via pattern recognition receptors (PRRs) and a subsequent influx of Ca²⁺ (Huang et al., 2022). This triggers a cascade of events involving Ca²⁺-dependent PKC, Raf-MEK-ERK pathway, NAPDH oxidase (NOX) phosphorylation, leading to ROS production (Hakkim et al., 2011; Dahlgren et al., 2019) (panel 4). The excessive ROS causes cytoplasmic granule degradation and release of elastase (NE) and myeloperoxidase (MPO) to the nucleus, along with peptidyl arginine deiminase 4 (PAD4), leading to chromatin decondensation and ultimately resulting in cell rupture and NETs release (Papayannopoulos et al., 2010) (panel 4). PKA phosphorylation of NOXA1 recruits 14-3-3 proteins, which block the assembly of NOX1 holoenzyme, ultimately preventing ROS production (Bokoch et al., 2009). Moreover, supraphysiological cAMP inhibits the formation of NETs and ROS burst (Eby et al., 2014). These findings highlight the role of cAMP signaling in inhibiting netosis via PKA. For further details, see text.