TNF-α-mediated downregulation of CD36 and phagocytic impairment of alveolar macrophages via upregulation of ADAM17 in asthma.

Background: Alveolar macrophages (AMs) are specialized phagocytes in the airways that play a crucial role in maintaining bronchoalveolar homeostasis through phagocytosis, the clearance of apoptotic cells. However, the characteristics and molecular mechanisms of AMs-mediated phagocytosis during the pathogenesis of asthma remain poorly characterized. Methods: An ovalbumin (OVA)-induced asthma model was established in mice through intraperitoneal sensitization followed by intranasal challenge. AMs were isolated from the bronchoalveolar lavage fluid of control and OVA-induced mice using adherence-based purification. The phagocytic capacity of AMs, as well as the expression levels of CD36 and ADAM17, were quantified by flow cytometry. Results: A significant reduction in both phagocytic efficiency and CD36 expression was found in the AMs of OVA-induced mice compared to control mice. Blockade of CD36 resulted in a marked decline in the phagocytic efficiency of normal AMs. Expression of ADAM17 was found to be notably elevated on the surface of AMs from OVA-induced mice compared to controls. Knockdown of ADAM17 led to a substantial increase in CD36 expression and a corresponding increase in phagocytic efficiency. Stimulation with tumor necrosis factor-α (TNF-α) resulted in a significant upregulation in ADAM17 and marked downregulation in CD36 expression levels, as well as impaired the phagocytic efficiency of AMs. Importantly, ADAM17 knockdown attenuated the TNF-α-mediated downregulation of CD36 expression and the associated impairment of phagocytic capacity in AMs. Conclusion: AMs from OVA-induced mice displayed significantly impaired phagocytic capacity. Airway TNF-α upregulated ADAM17, which in turn downregulated CD36 expression on AMs, ultimately suppressing their phagocytic function.