White blood cells receive ‘orders’ from our bodies to cause or subdue inflammation, a new paper reports, as a natural part of the immune response.

They argue that this effect can be used to prevent Acute Respiratory Distress Syndrome (ARDS), which affects some COVID-19 patients. ARDS is a type of respiratory failure caused by a buildup of fluid in the lungs.

Pimp my immune response

“We found that macrophage programming is driven by more than the immune system — it is also driven by the environment in which the macrophages reside,” said lead author Asrar Malik, the Schweppe Family Distinguished Professor and head of pharmacology and regenerative medicine at the University of Illinois at Chicago (UIC).

Macrophages are those immune cells that find a threat, wrap around it, and start digesting it. However, the new findings showcase that they also play a part in controlling inflammation. While a natural part of our bodies’ efforts against infection, and quite effective against them, excessive or prolonged inflammation can also damage our own tissues and organs.

In essence, these cells both cause and keep inflammation in check. The team analyzed how they determine which of the two approaches they use at any given time using mice. Their goal was to help patients suffering from excessive inflammation and conditions such as ARDS while infected with the coronavirus.

“We demonstrated that lung endothelial cells — which are the cells that line blood vessels — are essential in programming macrophages with potent tissue-reparative and anti-inflammatory functions,” said Dr. Jalees Rehman, UIC professor of medicine and pharmacology and regenerative medicine and co-lead author of the paper.

The researchers found that one protein, R-spondin-3, was present in high levels in the blood during injury and inflammation. The next step was to genetically-engineer lab mice to lack this protein in these cells — which led to the macrophages no longer dampening inflammation.

“Instead, the lungs became more injured,” said Bisheng Zhou, UIC research assistant professor of pharmacology and regenerative medicine and first author of the study. “We tried this in multiple models of inflammatory lung injury and found consistent results, suggesting that blood vessels play an important instructive role in guiding the programming of macrophages.”

The findings point the way towards a promising avenue of treatment for ARDS, but could also help us understand why some patients have better outcomes after a COVID-19 infection than others. Our own immune response has been shown to cause an important part of the damage associated with this disease. Poor vascular health or other underlying conditions that affect our blood vessels could impact our recovery, the team believes.

While the study only worked with lung tissue, it’s likely that those in other organs would show the same mechanisms, according to the authors.

The paper “The angiocrine Rspondin3 instructs interstitial macrophage transition via metabolic–epigenetic reprogramming and resolves inflammatory injury” has been published in the journal Nature Immunology.