DOCK2 CONTRIBUTES TO OBESITY-ASSOCIATED LUNG INJURY THROUGH REGULATING MACROPHAGE OXIDATIVE STRESS

Obesity is defined as the excessive fat accumulation that imposes many health concerns. DOCK2 promotes a proinflammatory phenotype of lung fibroblasts (LFs) to elicit lung injury in a chronic HFHF diet-induced obesity. Unlike wild-type (WT) mice, DOCK2 knockout mice showed reduced macrophage infiltration and reduced inflammation in the lungs after feeding a HFHF diet. A knowledge gap remains about the role of DOCK2 in mediating macrophage oxidative stress in obesity related lung injury. Since DOCK2 has been reported to mediate macrophage function in infection, based on the knowledge gap and DOCK2 function, a hypothesis was formed that DOCK2 mediates obesity related lung injury through regulating macrophage oxidative stress. We found that DOCK2 knockout reduced palmitic acid (PA)-induced oxidative stress in BMDMs. The induction of iNOS, MCP-1, and IL-6 by PA in WT BMDMs was blunted by DOCK2 knockout. Knockdown of DOCK2 using siRNA in WT BMDMs also attenuated the expression of these proteins. Further mechanistic study showed that DOCK2 knockout attenuated the activation of NF-κB and Rac1, which likely account for the inhibition of PA-induced oxidative stress in BMDMs. In vivo study showed that DOCK2 knockout reduced the expression of oxidative stress markers in the lungs of mice fed with a chronic HFHF diet. Together, our study demonstrated a critical role of DOCK2 in mediating macrophage-derived oxidative stress that potentially induces lung injury associated with obesity.