FIGURE 2.

The multi-step recruitment of leukocytes to the source of inflammation and the influence of exRNA at multiple sites during this process. In an inflammatory situation, either initiated by microbial agonists or in their absence (sterile inflammation), leukocytes in the blood stream approach the inflamed vessel wall to find the shortest way toward the source of inflammation/infection in the tissue. Following their capture on the vessel wall, leukocytes start rolling on the inflamed endothelium (indicated by stars) due to blood stream-mediated mechanical forces together with weak adhesive interactions between leukocytes and endothelial P- and E-selectins. Based on the close approximation of both cell types, heparan sulfate proteoglycan (syndecan)-fixed chemokines (such as Interleukin-8) can reach and activate their leukocytic receptors (inset) as well as induce “inside-out” activation of β2-integrins with the result that the tethered leukocytes become firmly attached to the vessel wall via ICAM-1 and start crawling toward the nearest point of emigration. The transmigration phase along a chemotactic gradient is also supported by β2-integrins, as is the subsequent recognition of complement-activated bacteria by leukocytes for the ultimate phagocytosis reaction within the inflamed tissue. This route of consecutive steps of immune cell recruitment is taken by neutrophils (within hours) and monocytes/macrophages (within a few days) to execute a proper immune response. Modified from Schymeinsky et al. (2011). Ribosomal extracellular RNA (exRNA) is capable of influencing cellular interactions at multiple sites during leukocyte recruitment (indicated by red numbers): (Tisoncik et al., 2012; Castanheira and Kubes, 2019). Fluid shear stress in the circulation can mediate liberation of exRNA from endothelial cells, and exRNA induces vascular permeability in a VEGF-receptor-2/neuropilin-1-dependent fashion as well as the release of components stored in Weibel–Palade granules. (Van Kaer et al., 2013) exRNA induces activation of leukocytes to acquire an adhesive phenotype and to release cytokines that further promote immune cell activation (Kolaczkowska and Kubes, 2013; Zindel and Kubes, 2020). As a consequence, exRNA-primed leukocytes are further promoted to firmly attach to the inflamed endothelium as a prerequisite for their transmigration. (Bianchi, 2007) exRNA can induce M1-polarization of monocytes/macrophages and thereby provoke a significant pro-inflammatory cytokine release by these cells. The details on exRNA-cell interactions in this context are outlined in the text.