Most of us had our knees bruised when we were kids: riding a bicycle, climbing the trees, playing soccer… and it was so fascinating to look at the tissue healing process following that – the development of fibrotic tissue, skin remodeling, and so on… Only much later in our life, did we come to know that internal organs can be wounded as well. So, now we posed the question – do our internal organs heal the same way as our skin? Fischer and colleagues from München, Germany, asked themselves that very question that brought them to a very interesting character in the play – neutrophil.
Let’s start with, what are wounds? Acute wounds (the common ones) would be defined by the healing process going through stages of inflammation, tissue formation, and remodeling. Fibroblasts migrate to the wound and locally synthesize and deposit the matrix ending with scar creation. If such normal repair fails, a chronic wound could occur. Chronic wounds are the ones where the healing is stuck in the inflammatory stage and, thus, become a burden to the patient. To research internal wound healing, Fischer and his colleagues tested the recovery of liver and peritoneum injury in mice.
Firstly, it was necessary to see if the matrix remodeling the wound was newly synthesized or transferred from nearby tissues. The researchers generated a non-labeled injured liver location but labeled a separate liver location. A signal showed up at a non-labeled location during the early stages of wound healing, indicating that the matrix was being transferred from other sites on the liver, and not newly synthesized. Consequently, the initially low fibroblast numbers grew after 2-3 days. This meant that, although initial repair was being done with transferred matrix, the process gradually developed into de-novo synthesis. By some more experimental injuring and labeling, it was seen that the matrix can migrate from the peritoneum to liver wounds, but not vice versa. Such outcome could be explained by different compositions of the proteins in each organ, and interestingly, that also determined if the repair would be scarring or scarless.
After multiple extra rounds of injuring and labeling, Fischer and the group confirmed that contrary to the expected, it is not fibroblasts that transfer to the matrix. It is our guy, the spiderman of the immuneverse – Neutrophil (they both eject “nets” after all).
By creating a sterile inflammation environment, myeloid cells with matrix fragments were spotted. The authors determined that myeloid cells carry, rather than synthesize, the matrix. Myeloid cells were seen migrating individually or in groups and some of the cells in the group had neutrophil expressing markers (e.g. CD64, CD66b, TNFr). Fisher and colleagues wanted to see what will happen if they deplete the neutrophils and macrophages. Only the neutrophil depletion blocked the matrix transfer.
High-resolution imaging did not show any vascular neutrophils which meant that transport was only occurring within the interstitial space of wounded organs. Specifically blocking chemokine receptors (CXCR2 and leukotriene receptor), blocked the transfer of the matrix. On the other hand, blocking the integrins inhibited matrix transport but not neutrophil migration. The researchers thus concluded that integrins are of importance for neutrophil matrix transfer into wounds.
Learning the specifics behind the mechanism of wound healing could be vital for translational research in patients with chronic injury, but how could this particular study be used by the pharma industry? Well, heat-shock signaling is a pharmacological target in fibrosis, and it causes integrin activation in neutrophils. By blocking heat-shock signaling, matrix transfer by neutrophils is also blocked. If such a procedure is used pharmacologically, excessive scarring could be prevented.
Even though this study is extremely fascinating, it is hard not to ask questions – how transferrable is it from a mouse model to a human? Is it possible to block the infinite inflammatory loop of chronic wounds? If yes, maybe then it is worth trying out. What do you think?
Fischer A, Wannemacher J, Christ S, Koopmans T, Kadri S, Zhao J, Gouda M, Ye H, Mück-Häusl M, Krenn PW, Machens HG, Fässler R, Neumann PA, Hauck SM, Rinkevich Y. Neutrophils direct preexisting matrix to initiate repair in damaged tissues. Nat Immunol. 2022 Apr;23(4):518-531. doi: 10.1038/s41590-022-01166-6.
Article author: Ines Poljak. Ines is a MSc graduate from University of Copenhangen who worked on multiple myeloma bone disease. She worked in several clinical laboratories before committing herself completely to research.
Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.
Check out Antibuddies’ blog post “Neutrophils help organs heal”.Tweet