The TAM receptor tyrosine kinases Axl and Mer drive the maintenance of highly phagocytic macrophages

Abstract

Many apoptotic thymocytes are generated during the course of T cell selection in the thymus, yet the machinery through which these dead cells are recognized and phagocytically cleared is incompletely understood. We found that the TAM receptor tyrosine kinases Axl and Mer, which are co-expressed by a specialized set of phagocytic thymic macrophages, are essential components of this machinery. Mutant mice lacking Axl and Mer exhibited a marked accumulation of apoptotic cells during the time that autoreactive and nonreactive thymocytes normally die. Unexpectedly, these double mutants also displayed a profound deficit in the total number of highly phagocytic macrophages in the thymus, and concomitantly exhibited diminished expression of TIM-4, CD163, and other non-TAM phagocytic engulfment systems in the macrophages that remained. Importantly, these previously unrecognized deficits were not confined to the thymus, as they were also evident in the spleen and bone marrow. They had pleiotropic consequences for the double mutants, also previously unrecognized, which included dysregulation of hemoglobin turnover and iron metabolism leading to anemia.

TAM receptors in phagocytosis: Beyond the mere internalization of particles

“…This included release of tissue repairinducing cytokines, inhibition of Toll-like receptors, and the arrest of the innate immune response . 1,16,24,28,37,[59][60][61] It is noteworthy to mention that while PtdSer is required for recognition of the apoptotic particles, its exposure alone is not sufficient to promote engulfment by macrophages. Segawa et al generated viable cells which overexpress and present PtdSer at comparable levels to those of ACs.…”

“…94,95 During the clonal expansion of thymocytes, autoreactive T cells must be eliminated to prevent autoimmune disorders, as well as hypo-reactive and inert T cells, as these are incompetent to carry out an immune response. 61,[96][97][98] Though to a lesser extent, the negative selection in the thymus continues for a small window of time postnatally, as the organ reduces its size and function. With puberty, both in humans and in mice the thymus undergoes involution, loses its cellular architecture, and produces less T cells as the organism ages.…”

“…Furthermore, Axl/Mertk double mutant mice display a 50% reduction in F4/80 + CD11b lo macrophages, which normally express MERTK and are highly efferocytic in the bone marrow and thymus, impairing apoptotic thymocyte clearance. 61 These macrophages are also responsible for continuously phagocytosing erythrocytes and their heme-iron components. In the absence of AXL and MERTK, the remaining macrophage subpopulations downregulate engulfment molecules such as CD163, further aggravating their phagocytic inefficiency.…”

“…Such TAM‐dependent anti‐inflammatory pathways were shown in dendritic cells (DCs) and macrophages, shifting their pro‐inflammatory profile to an overall anti‐inflammatory one. This included release of tissue repair‐inducing cytokines, inhibition of Toll‐like receptors, and the arrest of the innate immune response 1,16,24,28,37,59–61 …”

Editorial: Development of small molecule inhibitors and antibodies targeting AXL for tumor therapy and infectious disease control

“…High AXL expression in tumor cells promotes aggressiveness, metastatic capacity and refractoriness to drug treatment ( 11 , 12 ). In parallel, it was observed that the expression of AXL and other TAM receptors is higher in macrophages polarized towards the M2 anti-inflammatory pro-tumoral functional phenotype and that activation of AXL can induce M2 macrophages polarization ( 13 – 16 ). Since the M2 phenotype is typical of pro-tumoral tumor-associated macrophages, this points to AXL inhibition as a double target to reduce the aggressiveness of tumor cells and the tumor-promoting activity of the innate immune cells (macrophages).…”