Advanced glycation end products reduce macrophage‐mediated killing of Staphylococcus aureus by ARL8 upregulation and inhibition of autolysosome formation. Issue 8 (15th July 2020)

• Record Type: Journal Article
• Authors: Xie, Xiaoying; Yang, Chuan; Duan, Chaohui; Chen, Hongxing; Zeng, Tingting; Huang, Songyin; Li, Hongyu; Ren, Meng; Lin, Wei‐Jye; Yan, Li
• Is Part Of: European journal of immunology. Volume 50:Issue 8(2020)
• Page Start: 1174
• Page End: 1186
• Publication Date: 2020-07-15
• Subjects: Advanced glycation end products (AGEs) -- ARL8 -- Autophagy -- Macrophage -- Staphylococcus aureus; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201948477
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Staphylococcus aureus, a pathogen most frequently found in diabetic foot ulcer infection, was recently suggested as an intracellular pathogen. Autophagy in professional phagocytes like macrophages allows selective destruction of intracellular pathogens, and its dysfunction can increase the survival of internalized pathogens, causing infections to worsen and spread. Previous works have shown that S. aureus infections in diabetes appeared more severe and invasive, and coincided with the suppressed autophagy in dermal tissues of diabetic rat, but the exact mechanisms are unclear. Here, we demonstrated that accumulation of advanced glycation end products (AGEs) contributed to the diminished autophagy‐mediated clearance of S. aureus in the macrophages differentiated from PMA‐treated human monocytic cell line THP‐1. Importantly, infected macrophages showed increased S. aureus containing autophagosome, but the subsequent fusion of S. aureus containing autophagosome and lysosome was suppressed in AGEs‐pretreated cells, suggesting AGEs blocked the autophagic flux and enabled S. aureus survival and escape. At the molecular level, elevated lysosomal ARL8 expression in AGEs‐treated macrophages was required for AGEs‐mediated inhibition of autophagosome‐lysosome fusion. Silencing ARL8 in AGEs‐treated macrophages restored autophagic flux and increased S. aureus clearance. Our results therefore demonstrate a new mechanism, in which AGEs accelerate S. aureus immune evasion in macrophages by ARL8‐dependent suppression of autophagosome‐lysosome fusion and bactericidal capability. Abstract : Advanced glycation end products (AGEs) altered autophagic response in the host macrophages during S. aureus infection by promoting autophagosome formation but blocking the autophagosome‐lysosome fusion via an ARL8‐dependent mechanism, which diminished intracellular bactericidal capability of macrophages and likely resulted in increased invasiveness of S. aureus in diabetic foot infection .