Scientists are using zebrafish to understand the connection between the immune system and regeneration

The way the immune system responds to damage to many organs and tissues enables and enables their repair and regeneration. However, for some species, such as humans, damage to organs such as the head, spine or heart is irreversible. Imagine if we could restore them. Organ transplant candidates and recipients will no longer need to wait nervously for the “call” or the lifelong need for immunosuppressive drugs.

New research from the Storrs Institute for Medical Research used highly regenerative zebrafish to study the timing and genetic programming of macrophages, a type of white blood cell, in repair and regeneration zebrafish sense organ. Understanding how the immune system responds to injury, first by inducing inflammation and then an immediate anti-inflammatory response, provides invaluable knowledge for the development of targeted immunotherapies that can be used to combat human diseases such as hearing loss or deafness, heart or spinal cord injury .

Recently published in Communications of nature On September 20, 2022, doctoral student Nicholas Denance, Ph.D., discovered a new anti-inflammatory macrophage paradigm in the lab of Tatsiana Piatrovska, Ph.D. Rather than the conventional wisdom that the anti-inflammatory states of macrophage activation are linked to only one type of signaling pathway, Denance found that the same population can and must go through each of the three anti-inflammatory states to regenerate an organ.

“Organ regeneration offers an exciting opportunity for study immune system and wonder why some species can regenerate organs such as the heart or missing limbs, while others, like humans, cannot,” said Petrowski.

Zebrafish sensory hair cells are an ideal system for investigating pathways and cell types participate in regeneration, as they are easily destroyed by antibiotics and begin to regenerate within five hours. This allowed the researchers to determine the precise timing and genetic programs for each anti-inflammatory state of macrophage activation.

“Our hypothesis is that human macrophages are not receiving the proper chemical activation cocktail to instruct pro-regenerative processes,” Denance said. “Identifying the molecular recipe for macrophage activation in zebrafish may one day allow us to develop regenerative immunotherapy for humans.”

Necessary for organ regeneration, macrophages, which literally translates to “big eaters” in Latin, engulf foreign particles such as dead cells and bacteria and use enzymes to digest them. In addition to their culinary appetite, these cells signal both pro- and anti-inflammatory pathways to secrete chemicals or cytokines to either recruit additional types of white blood cells or trigger anti-inflammatory pathways to repair cells and tissues.

Study of macrophages high spatial resolution and at several closely spaced time points during the death and regeneration of zebrafish sensory hair cells was crucial. For the first time, the study demonstrates that a single population of cells of this type sequentially and independently passes through three different anti-inflammatory states, each with its own unique molecular and genetic signature.

“The new evidence is a valuable resource for comparativistics about the genetic programs involved in macrophage-mediated repair and regeneration,” Denance said. “In other words, different types of injury can trigger different kinds of inflammatory responses. We want to decipher whether this ‘language’ is universal or whether there are various dialects.’

Although the study marks the first time that the sequential states of macrophages have been resolved with extraordinary precision, preliminary comparisons with previously published pathways in different organs and species indicate that this mechanism is likely to be conserved.

“If you look in more detail, macrophages are not only necessary to initiate regeneration, but they also interact with the brain by interacting with nerve cells to restore and maintain the synapses necessary for the normal functioning of the organs after regeneration,” said Petrovsky.

The team hopes that further research based on this new finding could provide a basis for developing personalized immunotherapy to reduce the disease, perhaps by providing greater regenerative capacity in animals with limited regeneration, such as humans.

“This is just one of a series of steps to entertain the idea of ​​developing regenerative immunotherapy in humans,” Denance said.

Additional authors include Nhung TT Tran, Madeleine Suall, Daniel S. Diaz, and Jillian Blank.