FIGURE 2.

Self-amplification and self-limitation mechanisms that shape self-organized neutrophil swarming behavior. Multiple external signals can trigger neutrophils to release the swarm attractants LTB4 and CXCL2, which self-amplify the formation of neutrophils swarms. Several layers of self-generated signal amplification promote neutrophil swarming and clustering in a feed-forward manner (reviewed in detail in Glaser et al., 2021). This includes (1) a “calcium alarm signal” which propagates in nascent neutrophil clusters, which (2) triggers the release of LTB4 in early-arriving neutrophils. LTB4 acts as a signal relay molecule and acute signal to increase the radius of attraction and recruit more distant cells. Moreover, LTB4 and CXCL2 promote cell aggregation in the developing neutrophil cluster (3). In growing swarm aggregates, the neutrophil-secreted attractants LTB4 and CXCL2 accumulate gradually over time. Neutrophils respond to these high local concentrations of swarm attractants by desensitizing the corresponding swarm attractant receptors LTB4R1 and CXCR2. Desensitization is controlled by the GPCR kinase GRK2 and involves CXCR2 internalization, whereas desensitized LTB4R1 remains at the plasma membrane. Thus, GPCR desensitization serves neutrophils as cell-intrinsic mechanism to self-limit their swarming behavior.