Neutrophil in a blood smear.
Segmented_neutrophils.jpg: hematologist derivative work: patient-doc, CC BY-SA 3.0, via Wikimedia Commons
Auto-inflammatory diseases
There are many immune-mediated inflammatory diseases, including Crohn’s disease, rheumatoid arthritis, and lupus. These are not all the same type of immune disease. Lupus and rheumatoid arthritis are usually considered autoimmune diseases, while Still’s disease is often described as autoinflammatory, meaning the innate immune system is overactive.
In Still’s disease, some white blood cells release debris that the body treats as highly threatening. This post explores why neutrophils may help create a runaway snowball effect.
Neutrophils and cell debris
Neutrophils are one of the body’s first defenses against bacterial infection. These white blood cells can release a web-like material called a neutrophil extracellular trap, or NET. A NET contains a hodgepodge of bactericidal proteins, DNA, and other inflammatory molecules.
This mixture can trap and injure nearby microbes, but it also creates debris that the body must later clean up.
When neutrophils release debris too easily
This seems like a great use of neutrophils in our fight against invading bacteria. However, in patients with Still's Disease, researchers found something interesting.
Patients with Still's disease showed the following:
- Their blood showed elevated levels of NETs in the blood compared to controls
- Their neutrophils had a tendency to spontaneously form NETs
- Their neutrophils had an exaggerated response to stimulation, producing much more NET than healthy controls
In normal circumstances, the body can usually digest and clear NET “dust” before it becomes a major problem. However, there is another factor that makes spontaneous release and an exaggerated response problematic in patients with Still's Disease
When cell debris mimics bacterial DNA
The NET released by patients with Still's Disease has nucleic acid molecules (DNA) from mitochondria (mtDNA). NET-derived mtDNA is increased in patients compared to controls. Moreover, mtDNA can be a potent pro-inflammatory activator of macrophages. The latter cells go on to produce a slew of pro-inflammatory molecules (interleukins, like (IL)-1β, IL-6, IL-18).
Here's the thing: the DNA found in spontaneously released NETs was highly enriched for mtDNA compared with NETs from healthy control neutrophils. As expected, the plasma of patients also had higher levels of mtDNA than healthy controls.
This matters because mitochondrial DNA has bacterial-like features. Mitochondria evolved from ancient bacteria, so when mitochondrial DNA appears outside cells, the innate immune system may read it as a microbial danger signal.
Still’s disease: the snowball effect
- An ordinary infection takes place; any NET produced in healthy people is swept up like snowflakes.
- In predisposed patients, neutrophils release too much NET material. It is as if the snowflakes start sticking and form a snowball.
- The NET material contains mitochondrial DNA, which looks bacterial enough to alarm the innate immune system.
- Macrophages read the signal and release IL-1β.
- The body then recruits and primes more neutrophils.
- At some point, a threshold may be crossed: There are so many neutrophils recruited, all spontaneously releasing NET material, that the body has a huge snowball of neutrophils, macrophages, and other proinflammatory cells
- A PET scan in Still’s disease can show activation of immune-rich organs such as bone marrow, spleen, and lymph nodes.
- The body thinks there is ongoing infection, even though the “germ-like” signal is self-made.
Why IL-1 blockade can work so quickly
In Still’s disease, neutrophils appear more prone to releasing NET material, and that material may be unusually inflammatory because it contains mitochondrial DNA. Macrophages may read this mitochondrial DNA as a bacterial-like danger signal and respond by producing IL-1β and related cytokines. The result is a snowball: more IL-1, more neutrophil recruitment, more NET debris, and more inflammation.
This is why blocking IL-1 signaling with anakinra can rapidly quiet the system. It does not erase every NET. It cuts the main amplifier.
References:
- Hu Q, Shi H, Zeng T, Liu H, Su Y, Cheng X, Ye J, Yin Y, Liu M, Zheng H, Wu X, Chi H, Zhou Z, Jia J, Sun Y, Teng J, Yang C. Increased neutrophil extracellular traps activate NLRP3 and inflammatory macrophages in adult-onset Still's disease. Arthritis Res Ther. 2019 Jan 7;21(1):9. doi: 10.1186/s13075-018-1800-z. PMID: 30616678; PMCID: PMC6323819.
AI assistance note: I used ChatGPT as a thinking partner while developing this post, especially for exploring references on NETs, mitochondrial DNA, NLRP3 inflammasomes, and IL-1 signaling in Still’s disease. The final explanation and any remaining errors are my own.