Exploring the roles of atypical MAP kinases ERK3 and ERK4 during inflammation
Acute kidney injury is a complex event marked by renal tissue injury after ischemia or exposure to nephrotoxins. It is followed by the activation of intrarenal cells that trigger a stress response causing the infiltration of leukocytes that together help clear damaged tissue and later play a role in the healing process of the kidney. The mechanisms in which the immune system regulates events in AKI are not fully understood. Recent work has unveiled the key role of the atypical MAP kinases ERK3 and ERK4 in promoting inflammation, in part through regulating the synthesis of chemokines like CCL2 and CCL5 and playing a role in migration/invasion capabilities of immune cells to inflamed/damaged tissues. It is hypothesised that ERK3 and ERK4 activity promotes immune cell migration through intrinsic mechanisms and by fostering an inflammatory cascade. It is also believed that ERK3 and ERK4 promote immune cell maturation and activation and that blocking ERK3 and ERK4 activity can inhibit these processes. Using murine tubule epithelial kidney cells and bone marrow derived macrophages; we demonstrate that ERK3 deficiency attenuates the production of CCL2 and CCL5 in tubule cells stimulated with TNFα and TWEAK. Additionally, ERK3 loss does not impair bone marrow to mature into macrophages or polarize into pro-inflammatory or anti-inflammatory phenotypes. However, the absence of ERK3 in BMDMs inhibits their basal migration abilities in a scratch assay. Taken together, we provide evidence that TNFSF members may regulate ERK3 expression and play a role in the production of macrophage chemoattractant, which help foster the inflammatory cascade needed for macrophage infiltration. Moreover, we demonstrate that ERK3 plays a role in inherent ability for macrophages to migrate. All suggesting that ERK3 has multiple biological functions during inflammation.
ERK3 ERK4 inflammation CCL2 CCL5 macrophages migration atypical MAPK acute kidney injury