The Importance of Macrophages in Kidney Regeneration

Macrophages are demonstrably important in tissue regeneration. The process of regeneration is an intricate dance of signaling and activity carried out between stem and progenitor cells, somatic cells of varying types, senescent cells, and immune cells such as macrophages. The research of recent years strongly suggests that differences in macrophage behavior are in some way fundamental to the exceptional regeneration exhibited by species as diverse as salamanders, zebrafish, and spiny mice. Can macrophage behavior in our species be beneficially adjusted to improve regenerative capacity? Comparatively simple approaches aiming to shift macrophage polarization from the inflammatory, aggressive M1 polarization to the pro-regenerative M2 polarization appear quite promising in early animal studies, but this is just the tip of the iceberg. Much is left to be explored, and articles such as this one only underline the benefits that might be achieved given success.

Acute kidney injury, or AKI, is a devastating condition that develops in two-thirds of critically ill patients, and patients with AKI have a 60 percent risk of dying. In AKI, kidneys can become scarred and can show progressive decline in function, becoming unable to heal their tissue. During development in the womb, immune cells called macrophages go to the kidneys, and they remain there for life. Researchers have found that, during AKI in a mouse model, the kidney-resident macrophages are reprogrammed to a developmental state, resembling these same cells when they are found in newborn mice. Newborn mouse kidneys are still developing. This reprogramming during AKI may be important to promote healing and tissue regeneration. If a similar developmental shift is seen for human kidney-resident macrophages during AKI, that could aid new therapeutic approaches for patients.

Researchers detailed how the kidney-resident macrophages are reprogrammed to a developmental state after injury. In response to the disease model, the kidney-resident macrophages turned off their expression of major histocompatibility complex type II, or MHCII. This lack of expression is similar to kidney-resident macrophages in newborn mice - those mice, the researchers showed, lack expression of this protein up to postnatal day seven, and then begin to express it over the next two weeks. Notably, MHCII protein and macrophages have important roles in autoimmunity and transplant rejection.

In addition, kidney-resident macrophages after AKI underwent transcriptional reprogramming to express a gene profile closely resembling that of the kidney-resident macrophages in newborn mice at postnatal day seven. Further supporting their role in development and healing, the reprogrammed kidney-resident macrophages were enriched in Wnt signaling, an active pathway that is vital for mouse and human kidney development. Many basic science research studies have suggested the importance for tissue-resident macrophages in healing after injury, but development of therapies promoting them is still in early stages.



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