neutrophil chemotaxis

Neutrophils are the first of the innate immune system to arrive on the scene following tissue injury. This tremendous paper by McDonald and colleagues elegantly delineates the three-step process by which this happens.

First, using a thermal injury model that causes tissue necrosis (marked by propridium iodide, red), a labelled, soluble dextran that marks tissue vasculature (blue), the authors show that neutrophils hone expertly to the site of tissue necrosis primary via an intravascular, rather than an extravascular path (aka, they follow tracks marked by vasculature delineated in blue). The authors note that neutrophils take the longest possible intravascular tract, even at the expense of taking the shortest track; they hypothesize that this reduces potential collateral damage that could be exerted by neutrophils trafficking through healthy tissue on the way to a damaged focus.

The authors also show that tissue necrosis results in unique extracellular release of ATP, which is normally restricted to within cells. Extracellular ATP then activates the receptor P2X7-R on tissue-resident macrophages and stimulates them to produce pro-inflammatory cytokines such as IL-1B. Local endothelial cells then respond to this inflammation and upregulate expression of the integrin molecule ICAM-1; it is expression of these integrins which causes neutrophils to stick to the endothelium proximal to the necrotic focus; however, neither ATP nor IL-1B is responsible for actually attracting neutrophils to areas of necrosis, only adhesion at the focus.

Second, the authors then map out the pathway by which neutrophils arrive at the necrotic focus. The inflammation generated by tissue-resident macrophages drives expression of not only ICAM-1 but also the chemokinetic ligand MIP-2 (macrophage inflammatory protein 2), otherwise known as CXCL2. The authors clearly demonstrate that, unlike ICAM-1, MIP-2 is expressed on endothelial cells in a gradient that serves as a potent chemokinetic signal for neutrophils to the edge of the necrotic focus. Interestingly, however, the authors note that endothelial cells within 150 microns of the necrotic center do not express MIP-2, and neutrophils migrate in a pattern that is independent of exogenous MIP-2 expression in the necrotic center, suggesting that an overriding signal drives neutrophil chemotaxis within the proximal 150 microns of the necrotic focus.

Once neutrophils get within 150 microns of the necrotic focus, then what happens? The authors finally demonstrate that necrotic cells release so-called damage-associated molecular patterns (DAMPs), which are generated from fragments of cellular mitochondria. DAMPs share significant homology with pathogen-associated molecular patterns (PAMPs), which are derived from bacterial fragments; this should come as no surprise, as bacteria are thought to be evolutionary precursors of eukaryotic mitochondria. These DAMPs activate signaling through formylated peptide receptors on neutrophils, which serve as an overriding signal to drive the remaining migration of neutrophils to the necrotic focus.