Researchers at the Universities of Bonn and Sao Paulo have succeeded in curbing chronic inflammation in mice. They used customized “mini-antibodies” for this purpose. With these nanobodies, they succeeded in dissolving molecular complexes in the tissue that normally activate the immune system. It is possible that in the future the nanobodies produced could slow down unwanted inflammatory reactions that cause diseases such as arthritis or neurodegeneration.
Not only the villas of the rich and famous have a direct line to the police. The cells in our body also have a sophisticated alarm system, the inflammasome. Its central component is the so-called ASC molecule. In the event of danger – such as the attack of a pathogen – many of these protein compounds join together to form a large complex, the ASC speck. This ensures two things: First, its activity causes the cell to accumulate masses of messenger substances with which it can call on the immune system for help. And secondly, numerous pores are formed in the cell membrane through which these warning molecules can reach the outside and fulfill their task.
Last cry for help from the dying cell
These holes ultimately lead to the cell’s demise: “At some point, it virtually explodes and empties its entire contents into the tissue,” explains Prof. Dr. Bernardo Franklin from the Institute for Innate Immunity at the University Hospital Bonn. “The messenger substances that are now abruptly released then act like a last great cry for help. This triggers the immune system to mount a strong inflammatory response that contains the infection.” This is why this mechanism of innate immune defense is also immensely important.
However, ASC specks also enter the tissue in the process and can persist there for a long time under certain circumstances. “We have now been able to show in mice that their activity activates the immune system even after the threat has been averted,” Franklin says. “The result can be chronic inflammation that severely damages the tissue.” Together with researchers from the University of Sao Paulo, Franklin’s team has succeeded in preventing this undesirable effect. For this purpose, they used so-called nanobodies.
These agents are antibody fragments with a very simple structure. “In collaboration with Prof. Dr. Florian Schmidt of the Institute of Innate Immunity, we generated nanobodies that specifically target ASC and can dissolve the specks,” explains Franklin’s collaborator Dr. Damien Bertheloot. The researchers enlisted the help of an alpaca: they injected the animal with the ASC protein so that it developed antibodies that matched it. Some of the alpaca antibodies have a very simple structure. This allows fragments of these antibodies to be produced and tested as so-called nanobodies.
Rheumatism and gout symptoms relieved in mice
The researchers were able to obtain the genetic information for the ASC nanobodies from blood samples of the animal using a complex procedure. “We then incorporated this genetic makeup into bacteria so that we could have them produce the nanobody in large quantities,” Bertheloot explains. The proof that the compound can dissolve ASC specks was provided by the team in human cell cultures, but also in mice. “In our experiments, the mice have rheumatoid and gout-like symptoms,” Bertheloot explains. “After administration of the nanobody, the inflammation and also the health of the rodents improved significantly.”
Nanobodies are very small compared to normal antibodies. Therefore, they are excellent for resolving such molecular complexes. This is because they can still reach places where it would be too crowded for large active ingredients. Moreover, normal antibodies additionally stimulate the immune system and can therefore exacerbate inflammation – a property that nanobodies lack.
The results are also interesting for another reason: studies indicate that ASC specks can also cause significant damage in the brain. There, they seem to serve as a kind of “crystallization nucleus” for the protein Aß. In the brains of Alzheimer’s patients, Aß clumps together to form large protein complexes called plaques. Presumably, ASC bacon can trigger this clumping. “Perhaps it is therefore possible to slow down this process with the help of our nanobodies,” hopes Franklin, a member of the ImmunoSensation2 cluster of excellence at the University of Bonn. “We now plan to investigate this possibility in a follow-up study.”
At the same time, however, he warns against overly high expectations: Even in the ideal case, it will be years before the results possibly lead to new drugs.
Original publication:
Damien Bertheloot et al: Nanobodies dismantle post-pyroptotic ASC specks and counteract inflammation in vivo; EMBO Molecular Medicine; DOI: https://doi.org/10.15252/emmm.202115415
