Axl receptor-mediated efferocytosis plays an essential role in maintaining brain homeostasis

The phagocytosis of apoptotic bodies, a process called efferocytosis, plays a fundamental role in maintaining tissue homeostasis by preventing secondary necrosis and excessive inflammation. This process involves the recruitment of phagocytes, such as macrophages, and the recognition of apoptotic cells through "Eat-me" signals, including the exposure of phosphatidylserine on the outer leaflet of the plasma membrane. Efferocytosis is mediated by several receptors, including the TAM receptor family (Tyro3, Axl and MerTk), which recognize apoptotic cells indirectly through Gas6 and Protein S and promote the inhibition of pro-inflammatory signaling pathways, such as cytokine and Toll-like receptors. In the brain, efferocytosis is primarily performed by microglia, and alterations in this process may contribute to the development of neuroinflammation, and neurodegenerative diseases. Here, we investigated whether Axl receptor-mediated efferocytosis deficiency alters brain immune homeostasis. Brain cell suspensions from WT and Axl-/- mice were analyzed by flow cytometry or RT-qPCR and the cytokine levels were assessed by ELISA. We observed that the Axl-/- mice showed alterations in brain immune populations, including increased frequencies of total myeloid cells, particularly monocytes, as well as lymphocytes, and microglia. Microglia from Axl-/- mice also exhibited reduced CX3CR1 expression compared to WT. In addition, we observed lower frequencies of macrophages and neutrophils in the brains of Axl-/- mice compared to WT. At the transcriptional level, Axl-/- mice showed increased expression of Cxcl1, Il-6, Tgfb, Gas6, Socs3 and Caludin-2. Despite these transcriptional alterations, no diferences were detected in the cytokine levels of IL-6, TNF, CXCL1 and IL-10 in the brains of Axl-/- mice. Overall, these data suggest that Axl deficiency alters cellular and molecular features of brain immune homeostasis, which may influence the response to subsequent inflammatory challenges.