Neutrophils secrete exosome-associated DNA to resolve sterile acute inflammation

Acute inflammation is the body’s rapid response to injury or infection, and neutrophils—our first-responder immune cells—are key players in this process. But what happens when inflammation needs to be dialed down? A new study from the University of Michigan offers new insights into how neutrophils help resolve inflammation using an unexpected tool: DNA.

Previous research showed that neutrophils release lipid-based signaling molecules like LTB4 in tiny packages called exosomes to promote immune cell infiltration. In this new work, Arya and colleagues discovered that these exosomes also carry nuclear DNA, released not during cell death, but while the neutrophils are still alive and actively moving toward the site of inflammation.

The researchers found that DNA is packaged into multivesicular bodies derived from the nuclear envelope, a process driven by the lamin B receptor and chromatin decondensation. This controlled DNA release is distinct from the well-known neutrophil extracellular traps (NETs), which involve the cell essentially self-destructing to trap pathogens.

Spatial co-occurrence of nuclear DNA with NE-derived exosomes
secreted from activated neutrophils

a, An overlay image of PMNs on fibrinogen-coated Quantifoil grids stimulated with 100 nM LTB₄ for 15 min in the presence of SYTOXgreen and vitrified, showing the reflected light (grey) and extracellular DNA (green). Dashed yellow lines highlight PMNs on the grid square. Representative of two biological replicates. Scale bar, 10 μm. b, A low-magnification transmission electron microscopy (TEM) image (×6,500) of the highlighted region (red box) in a is overlaid with the SYTOXgreen fluorescence signal. The cyan box indicates the area where cryo-ET data were acquired. Scale bar, 500 nm. c, A slice through the tomogram of the region highlighted (cyan box) in b, with insets showing bead-on-string-like structures (yellow arrowheads), proximal to extracellular vesicles (EVs) highlighted by black arrows. Scale bars, 100 nm and 10 nm in the insets. d, Segmentation of vesicles (<100 nm in orange/pink, >100 nm in olive green) and the DNA (cyan) corresponding to the tomogram in c. Scale bar, 100 nm. See associated Supplementary Video 1. e, Western blots representative of three independent experiments showing FLAP, 5LO and histone H3 in the exosomes purified from LTB₄-activated PMNs and treated with 50 µg ml⁻¹ rDNase I. f, Bar graph showing the quantifications of FLAP, 5LO and histone H3 band intensity in control and rDNase I-treated exosome samples. Data points (red dots) from three independent experiments were plotted as mean ± s.e.m. P values determined using two-way ANOVA are reported. g, Schematic illustration of DNA packaging and secretion during the nuclear budding and the fusion of NE-MVB with the PM. Note the change in the orientation of the LBR N-terminal Tudor domain as it moves from the inner nuclear membrane to the PM. Source numerical data and unprocessed blots are available in the source data file.

Why does this matter? In mouse models of sterile skin inflammation, the DNA-containing extracellular vesicles actually helped resolve inflammation, suggesting that neutrophils not only initiate the immune response but also help bring it to a close in a highly coordinated, non-destructive manner.

This research opens up fascinating new avenues for understanding chronic inflammation and immune regulation, especially the role of extracellular vesicles in carrying non-traditional cargo like DNA.