Epigenetic emergency switch improves defense against infections

During infections, the hematopoietic system switches from normal mode to emergency mode. It improves defense against pathogens. Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now discovered an epigenetic switch in mouse blood stem cells and progenitor cells that triggers a switch from one mode to another.

If the emergency program of hematopoiesis begins in the body, this indicates an alert state of the immune system and serves two different purposes: compared to “normal mode” hematopoiesis, the emergency program causes an increased replenishment of immune cells that are consumed during nutrition. infections or inflammations. In addition, the emergency program puts the entire immune system into pre-activation, which helps to eliminate infections faster.

Features of the emergency program are, for example, an increase in the rate of division of blood stem cells and a change in the balance of mature white blood cells in favor of myeloid cells (macrophages and granulocytes). Normally, the emergency program is triggered by molecular components specific to pathogens or by pro-inflammatory messenger substances such as certain interferons.

But what happens in blood stem cells and progenitor cells? Is there a mobile link that triggers an emergency app? Scientists led by Nikolaus Dietlein and Hans-Reimer Rodewald from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) targeted a specific epigenetic modification that shortens H2Bub1. It is involved in the activation of genes that are activated by interferon after viral infection and are important for defense against infection. The modification, which binds to the DNA packaging proteins, histones, is removed again by the USP22 enzyme.

Could H2Bub1 and USP22 be the sought-after switch that activates the emergency program in the blood stem cell? Researchers led by Rodewald studied this in mice genetically defective in USP22 blood stem cells. In these animals, the emergency hematopoiesis program continued with all its essential features without any detectable infection or increased interferon levels.

Genetically modified animals were able to fight infection with Listeria monocytogenes better than normal mice. In addition, important cleaning cells in their blood, neutrophil granulocytes, were more successful at engulfing the bacteria.

As expected, the genetic material in the blood cells of the genetically modified animals also showed significantly more H2Bub1 epigenetic modification. “Elevated levels of H2Bub1 appear to be an alarm button that shuts down the immune system. In particular, it puts the innate immune defense on heightened defensive alert, which is particularly important during initial contact with a pathogen,” says Nikolaus Dietlein, first author of the current publication. USP22, which removes the H2Bub1 modification, stops alerting in normal animals.

H2Bub1 and USP22 are also present in human cells and, according to the present study, perform functions there that are comparable to those in mice. Hans-Reimer Rodewald says: “We were able to show that epigenetic modification in mice improves defense against infection. However, how loss of USP22 affects human hematopoietic stem and progenitor cells remains unknown and now needs to be investigated. USP22 by drugs may one day help improve immune defenses against pathogens. However, to date this has not yet been proven and needs to be tested in future studies.

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