Neutrophils: Amoeboid Migration and Swarming Dynamics in Tissues

Abstract

Neutrophils are key cells of our innate immune response with essential roles for eliminating bacteria and fungi from tissues. They are also the prototype of an amoeboid migrating leukocyte. As one of the first blood-recruited immune cell types during inflammation and infection, these cells can invade almost any tissue compartment. Once in the tissue, neutrophils undergo rapid shape changes and migrate at speeds higher than most other immune cells. They move in a substrate-independent manner in interstitial spaces and do not follow predetermined tissue paths. Instead, neutrophil navigation is largely shaped by the chemokine and chemoattractant milieu around them. This highlights the decisive role of attractant-sensing G-protein coupled receptors (GPCRs) and downstream molecular pathways for controlling amoeboid neutrophil movement in tissues. A diverse repertoire of cell-surface expressed GPCRs makes neutrophils the perfect sentinel cell type to sense and detect danger-associated signals released from wounds, inflamed interstitium, dying cells, complement factors or directly from tissue-invading microbes. Moreover, neutrophils release attractants themselves, which allows communication and coordination between individual cells of a neutrophil population. GPCR-mediated positive feedback mechanisms were shown to underlie neutrophil swarming, a population response that amplifies the recruitment of amoeboid migrating neutrophils to sites of tissue injury and infection. Here we discuss recent findings and current concepts that counteract excessive neutrophil accumulation and swarm formation. In particular, we will focus on negative feedback control mechanisms that terminate neutrophil swarming to maintain the delicate balance between tissue surveillance, host protection and tissue destruction.

Keywords: GPCR; amoeboid migration; chemoattractants; infection; inflammation; neutrophil; receptor desensitization; swarming.

FIGURE 1

Migration patterns of neutrophils in inflamed skin tissue. (A) Amoeboid migrating neutrophils (blue) move rapidly and with polarized morphologies in the interstitial space of diffusely inflamed tissues. The cell trajectories indicate non-directional movement patterns within the collagen bundle scaffold of the dermal interstitium. (B) When the inflammatory stimulus dissipates, neutrophils slow down, and eventually lose their polarized morphology and stop migrating. (C) However, these neutrophils stay responsive and can still react quickly to acute damages, e.g., a laser-induced tissue injury. Neutrophils in the vicinity of a tissue lesion rapidly polarize and migrate in direction toward the damage site, before a few minutes later swarming is induced and more neutrophils are recruited to form local neutrophil clusters.

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.