Chemokine Signaling and the Regulation of Bidirectional Leukocyte Migration in Interstitial Tissues

Abstract

Summary Motile cells navigate through complex tissue environments that include both attractive and repulsive cues. In response to tissue wounding, neutrophils, primary cells of the innate immune response, exhibit bidirectional migration that is orchestrated by chemokines and their receptors. Although progress has been made in identifying signals that mediate the recruitment phase, the mechanisms that regulate neutrophil reverse migration remain largely unknown. Here, we visualize bidirectional neutrophil migration to sterile wounds in zebrafish larvae and identify specific roles for the chemokine receptors Cxcr1 and Cxcr2 in neutrophil recruitment to sterile injury and infection. Notably, we also identify Cxcl8a/Cxcr2 as a specific ligand-receptor pair that orchestrates neutrophil chemokinesis in interstitial tissues during neutrophil reverse migration and resolution of inflammation. Taken together, our findings identify distinct receptors that mediate bidirectional leukocyte motility during interstitial migration depending on the context and type of tissue damage in vivo.

Citrullination regulates wound responses and tissue regeneration in zebrafish

“…It is unclear if this phenotype is due to a failure of wound resolution or potentially a direct effect of citrullination on leukocyte signaling pathways. Binding of the neutrophil chemokine, Cxcl8, to its receptors, Cxcr1 and Cxcr2, regulates neutrophil directional and reverse migration (Powell et al, 2017); interestingly, citrullination of Cxcl8 alters its binding to its receptors (Proost et al, 2008). Alternatively, citrullination of ECM components affects cell migration (Shelef et al, 2012; Sipilä et al, 2014; Yuzhalin et al, 2018), and could potentially regulate inflammation by altering the wound ECM.…”

Chemotaxis and topotaxis add vectorially for amoeboid cell migration

“…This observation is not only relevant for in vitro applications, like tissue engineering 46 and cell sorting 47 , but also when studying amoeboid migration in vivo. Recent examples of such studies are on leukocyte migration 30 and on the detachment of tumor cells 48 . While these in vivo studies usually focus on chemotaxis, our results suggest that an additional topotactic influence has to be considered as a key factor, and that it even might be necessary to correct for any of its effects.…”

“…Such environments are encountered by highly motile cells navigating entire tissues, like macrophages during immune response and metastasizing amoeboid sarcoma cells. For example, recent studies of neutrophil movement inside Zebra fish larvae map migratory patterns across the fish tail following a chemotactic response 29,30 . The migration of these cells is effectively a (biased) random walk through a crowded environment.…”

Docosahexaenoic acid slows inflammation resolution and impairs the quality of healed skin tissue

“…The inflammatory phase of the wound healing is divided into initial and late responses [3]. The initial inflammatory response involves an increase in vascular permeability to facilitate migration of neutrophils and macrophages; an increase in phagocytosis that aims to clean the injured site; and the production of cytokines and chemokines that amplifies the migration of inflammatory cells and orchestrates the synthesis of new tissue [4,5]. On the other hand, the late response is characterized by an increase in the production of pro-resolving molecules such as interleukin-10 (IL-10) and fatty acid-derived lipid mediators that will orchestrate a reduction in pro-inflammatory markers [4,5].…”