Neutrophils cascading their way to inflammation

Abstract

Neutrophils are pivotal effector cells of innate immunity. Their recruitment into peripheral tissues is indispensable for host defense. Given their destructive potential, neutrophil entry into tissue must be tightly regulated in vivo to avoid damage to the host. An array of chemically diverse chemoattractants is active on neutrophils and participates in recruitment. Neutrophil chemoattractants were thought redundant in the control of neutrophil recruitment into peripheral tissue, based on their often indistinguishable effects on neutrophils in vitro and their frequently overlapping patterns of expression at inflammatory sites in vivo. Recent data, however, suggest that neutrophil chemoattractants have unique functions in the recruitment of neutrophils into inflammatory sites in vivo, dictated by their distinct patterns of temporal and spatial expression.

Figure 1. Regulation of neutrophil egress from the bone marrow by CXCR4 and CXCR2 chemokine ligands

The CXCR4 ligand SDF-1 (CXCL12) functions to retain neutrophils in the bone marrow, while the CXCR2 ligands KC (CXCL1) and MIP-2 (CXCL2) promote neutrophil egress. GCSF mobilizes neutrophils from the bone marrow by increasing the ratio of CXCR4 to CXCR2 ligands in the bone marrow. Neutrophil egress is influenced by the local production of G-CSF and KC within the bone marrow as well as the release of these mediators from inflamed peripheral tissues.

Figure 2. Recruitment of neutrophils into the joint in immune complex-induced arthritis is mediated by a temporal cascade of chemoattractants

(1) At early time points, LTB₄ is required to recruit and activate a small number of neutrophils. (2) These recruited neutrophils release IL-1β in the joint, which induces the release of predominantly CCR1 ligands at first and later CXCR2 ligands from cells in the joint. (3) CCR1 ligands are required to recruit the next wave of neutrophils into the joint, and this recruitment of neutrophils is broadly amplified in the last step of the cascade when (4) CXCR2 ligands released form neutrophils themselves potently recruit large numbers of neutrophils into the joint.

Figure 3. Recruitment of neutrophils into a sterile necrotic site is mediated by a spatial cascade of chemoattractants

(1) Necrotic tissues release DAMPs and ATP, which induce the release of IL-1β from resident tissue macrophages. (2) Secreted IL-1β induces the intravascular expression of ICAM-1, resulting in the adhesion of neutrophils to the endothelium surrounding the necrotic focus. Zones of chemoattractants are formed at different distances from the necrotic focus that sequential guide neutrophil migration into the lesion. (3) Farthest from the necrotic focus, a gradient of CXCR2 ligands is induced in the vasculature that guides neutrophils to the vicinity of the necrotic focus. (4) This chemokine gradient falls off close to the necrotic site, and neutrophils are then guided into the necrotic site by a gradient of FPRL1 ligands released from dying cells.