Abstract
Simple SummaryThe functions of animal and human cells depend on the actin cytoskeleton and its regulating protein called the RhoA. The actin cytoskeleton and RhoA also regulate the response of the immune cells such as macrophages to the microbial invasion and/or the presence of a non-self, such as a transplanted organ. The immune response against transplant occurs in several steps. The early step occurring within days post-transplantation is called the acute rejection and the late step, occurring months to years post-transplantation, is called the chronic rejection. In clinical transplantation, acute rejection is easily manageable by the anti-rejection drugs. However, there is no cure for chronic rejection, which is caused by the macrophages entering the transplant and promoting blockage of its blood vessels and destruction of tissue. We discuss here how the inhibition of the RhoA and actin cytoskeleton polymerization in the macrophages, either by genetic interference or pharmacologically, prevents macrophage entry into the transplanted organ and prevents chronic rejection, and also how it affects the anti-microbial function of the macrophages. We also focus on the importance of timing of the macrophage functions in chronic rejection and how the circadian rhythm may affect the anti-chronic rejection and anti-microbial therapies.The small GTPase RhoA, and its down-stream effector ROCK kinase, and the interacting Rac1 and mTORC2 pathways, are the principal regulators of the actin cytoskeleton and actin-related functions in all eukaryotic cells, including the immune cells. As such, they also regulate the phenotypes and functions of macrophages in the immune response and beyond. Here, we review the results of our and other’s studies on the role of the actin and RhoA pathway in shaping the macrophage functions in general and macrophage immune response during the development of chronic (long term) rejection of allografts in the rodent cardiac transplantation model. We focus on the importance of timing of the macrophage functions in chronic rejection and how the circadian rhythm may affect the anti-chronic rejection therapies.
Highlights
Over the years, organ transplantation became the ultimate savior for patients with a fatal organ failure
It is well established that actin polymerization and polymerization/depolymerization dynamics are regulated by the small GTPase RhoA and Rac1, their downstream effectors, and the interacting pathways, such as guanine nucleotide exchange factors (GEFs), and a rapamycin-insensitive protein complex 2 [7,8]
We showed that the commercially available RhoA pathway inhibitors, such as Y27632, Fasudil, Azaindole, or clinically approved for the treatment of multiple sclerosis Fingolimod and Siponimod, administered to the recipient, three or four times within one week of transplantation, abrogate chronic rejection of mouse and rat cardiac allografts (Figure 5)
Summary
Organ transplantation became the ultimate savior for patients with a fatal organ failure. The adaptation and translation of the results and conclusions from the rodent studies to humans are limited by the interspecific differences, and the great disparity in the lifespan, rodent models can provide the basis for eventual clinical testing in humans. Another limitation is that the therapeutic drugs used in the animal models are usually unapproved for human use. The results of our studies in the rodent transplantation model showed that many commercially available—but clinically unapproved—RhoA/ROCK inhibitors were very effective in the prevention of chronic rejection of the transplants. Besides the opportunity to study and manipulate macrophage immune response to transplantation, the rodent transplantation models are very useful for the studies of universal macrophage functions and their regulatory molecules, far beyond the bounds of transplantation
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