Ligation of FcγR Alters Phagosomal Processing of Protein via Augmentation of NADPH Oxidase Activity

Abstract

Proteolysis and the reduction of disulfides, both major components of protein degradation, are profoundly influenced by phagosomal redox conditions in macrophages. We evaluated the activation of phagocytic receptors that are known to influence activation of the phagocyte NADPH oxidase (NOX2), and its effect on phagosomal protein degrada- Phagocytosis is necessary for the destruction of pathogens, the clearance of cellular debris and the processing of exogenous protein antigen. While the hydrolysis of phagocytosed protein is not generally considered an effective antimicrobial effector, it is essential to the recycling of proteins during tissue remodeling and repair as well as the processing of major histocompatibility complex (MHC)-restricted antigens. The efficient degradation of phagocytosed protein requires the reduction of interand intra-molecular disulfides [predominantly mediated by gamma interferon-inducible lysosomal thioreductase (GILT)] and the hydrolysis of peptide bonds by lysosomal † Co-first authors.proteases such as the lysosomal cathepsins (1,2). The activities of GILT and the lysosomal proteases are not only regulated by their expression and delivery to the phagosome but also by local conditions such as pH and redox chemistries within the phagosomal microenvironment (3). Of particular note, reactive oxygen species (ROS) generated by the phagocyte NADPH oxidase (NOX2) can directly oxidize the active-site cysteines present in thiol-dependent proteases and disulfide reductases, which can dramatically decrease the efficiencies of both proteolysis and disulfide reduction of phagocytosed protein (4,5). Controlling protein degradation at multiple levels allows macrophages to fine-tune phagosomal function in response to various environmental and immune stimuli 786 www.traffic.dk

Triggering MSR1 promotes JNK‐mediated inflammation in IL‐4‐activated macrophages

“…Recent data imply that distinct pathways regulate uptake kinetics of different particles as well as phagosome functions in macrophages, and these are further controlled by macrophage activation. It was demonstrated that both the phagocytic receptors (Dill et al , ; Balce et al , ) and pro‐inflammatory (Yates et al , ; Trost et al , ; Ghigo et al , ) and anti‐inflammatory activation (Varin et al , ; Balce et al , ) of macrophages affect phagosome functions and these are regulated by signalling pathways such as kinases (Hartlova et al , ) and E3 ligases (O. Bilkei‐Gorzo, T. Heunis, A. Härtlova, M. Trost, unpublished data ).…”

IFNγ Enhances CD64-Potentiated Phagocytosis of Treponema pallidum Opsonized with Human Syphilitic Serum by Human Macrophages

“…Second, upregulation of baseline TLR2 and TLR8 expression by IFNγ, as shown herein, could promote more opportunities for ligation of released spirochetal PAMPs (33, 53) and TLR signaling itself may lead to a more rapid maturation of the phagosome (68). Alternatively, as shown by Balce et al (69) FcγR-mediated phagocytosis in association with IFNγ could facilitate phagosomal processing of proteins. IFNγ stabilizes MyD88 (70), in addition to modulation of the FcγR signaling cascade (59, 71), helping to enhance the recognition response to Tp .…”

Reactive Oxygen Species in Autoimmune Cells: Function, Differentiation, and Metabolism

“…In addition, alloantibody-FcγR I/FcγR III-dependent ROS production in macrophages is an important mediator of humoral immune damage during liver graft rejection (27). Opsonization of IgG on IFN-γ-activated macrophages led to diminished phagosomal processing of proteins in a PKC/Syk-NOX2dependent manner, which occurs at the level of the individual phagosome (28). Altered IgG subtype distribution and the resulting increase in IFN-γ production are observed in both patients with CGD and a CGD mouse model (29), indicating a possible feedback loop involving IFN-γ, IgG, FcγRs, and NOX2.…”

“…Apoptotic neutrophils cargo contributes to activation of macrophage NOX2 in a CD11b-TLR2/TLR4-myeloid differentiation primary response 88 (MyD88)-dependent manner and the subsequent ROS production, which is significantly delayed in macrophages from NOX2-deficient mice (46). While IgG-opsonized antigen cargo activates NOX2 dependent on FcγR-PKC/Syk pathway rather than V-ATPase (13,28,46).…”