Rab26 promotes macrophage phagocytosis through regulation of MFN2 trafficking to mitochondria

Acute respiratory distress syndrome (ARDS) is an inflammatory disorder of the lungs caused by bacterial or viral infection. Timely phagocytosis and clearance of pathogens by macrophages are important in controlling inflammation and alleviating ARDS. However, the precise mechanism of macrophage phagocytosis remains to be explored. Here, we show that the expression of Rab26 is increased in Escherichia coli‐ or Pseudomonas aeruginosa‐stimulated bone marrow‐derived macrophages. Knocking out Rab26 reduced phagocytosis and bacterial clearance by macrophages. Rab26 interacts with mitochondrial fusion protein mitofusin‐2 (MFN2) and affects mitochondrial reactive oxygen species generation by regulating MFN2 transport. The levels of MFN2 in mitochondria were reduced in Rab26‐deficient bone marrow‐derived macrophages, and the levels of mitochondrial reactive oxygen species and ATP were significantly decreased. Knocking down MFN2 using small interfering RNA resulted in decreased phagocytosis and killing ability of macrophages. Rab26 knockout reduced phagocytosis and bacterial clearance by macrophages in vivo, significantly increased inflammatory factors, aggravated lung tissue damage, and increased mortality in mice. Our results demonstrate that Rab26 regulates phagocytosis and clearance of bacteria by mediating the transport of MFN2 to mitochondria in macrophages, thus alleviating ARDS in mice and potentially in humans. Rab26‐mediated transport of mitochondrial fusion protein mitofusin‐2 (MFN2) from the cytoplasm to mitochondria promotes production of reactive oxygen species (ROS) during phagocytosis of bacteria by macrophages and subsequently results in phagocytosis and clearance of the bacteria. Rab26 deficiency impairs phagocytosis of bacteria by macrophages through reducing localization of MFN2 in mitochondria and ROS generation. This exacerbates the inflammatory response and lung tissue damage in acute respiratory distress syndrome.