The dynamic uptake and release of SOD3 from intracellular stores in macrophages modulates the inflammatory response

Abstract

Superoxide dismutase 3 (SOD3) is an extracellular enzyme with the capacity to modulate extracellular redox conditions by catalyzing the dismutation of superoxide to hydrogen peroxide. In addition to synthesis and release of this extracellular protein via the secretory pathway, several studies have shown that the protein also localizes to intracellular compartments in neutrophils and macrophages. Here we show that human macrophages release SOD3 from an intracellular compartment within 30 min following LPS stimulation. This release acutely increases the level of SOD3 on the cell surface as well as in the extracellular environment. Generation of the intracellular compartment in macrophages is supported by endocytosis of extracellular SOD3 via the LDL receptor-related protein 1 (LRP1). Using bone marrow-derived macrophages established from wild-type and SOD3 −/− mice, we further show that the pro-inflammatory profile established in LPS-stimulated cells is altered in the absence of SOD3, suggesting that the active release of this protein affects the inflammatory response. The internalization and acute release from stimulated macrophages indicates that SOD3 not only functions as a passive antioxidant in the extracellular environment, but also plays an active role in modulating redox signaling to support biological responses.

Changes in the Activity and Concentration of Superoxide Dismutase Isoenzymes (Cu/Zn SOD, MnSOD) in the Blood of Healthy Subjects and Patients with Acute Pancreatitis

“…SOD3 is known as a predominant form of SODs in plasma [ 10 ]. In many studies, it has been shown that SOD3 is mainly expressed in endothelial cells [ 11 , 26 , 27 ], and its decrease was associated with vascular endothelium damage and the infiltration of inflammatory cells [ 5 , 10 , 28 ]. In our previous study [ 29 ], we demonstrated an increased concentration of endothelium damage markers in AP patients which could be associated with decreased SOD3 concentration in the plasma of these patients.…”

“…SOD3 is the extracellular superoxide dismutase which has unique characteristics and functions in the cellular signal transduction [ 1 , 10 ]. Recent studies have also shown that SOD3 can be localized in intracellular compartments in neutrophils and macrophages [ 11 ]. It is highly expressed in certain tissues, such as cardiovascular endothelium, placenta and lung, and moderately within kidney, pancreas and uterus, cartilage, skeletal muscle, adipose tissue, brain and eye [ 4 , 12 ].…”

“…It is highly expressed in certain tissues, such as cardiovascular endothelium, placenta and lung, and moderately within kidney, pancreas and uterus, cartilage, skeletal muscle, adipose tissue, brain and eye [ 4 , 12 ]. This homotetrameric glycoprotein, due to the presence of a positively charged C-terminal region in its structure, is capable of binding proteoglycans contained in the cell membrane and constituents of the extracellular matrix [ 11 ].…”

Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages

“…This release is accompanied by a reduced level of superoxide in the extracellular space and hence modulated redox conditions [ 57 , 59 ]. Macrophages can internalize recombinant SOD3 for storage, implicating a sorting step for deviation from the archetypical endosomal traffic to lysosomes [ 60 ]. In contrast to neutrophils that establish secretory vesicles by bulk membrane endocytosis, the uptake of SOD3 in macrophages appears to be mediated by the specific interaction with the cell surface receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which is highly expressed in macrophages [ 60 , 61 ].…”

“…Macrophages can internalize recombinant SOD3 for storage, implicating a sorting step for deviation from the archetypical endosomal traffic to lysosomes [ 60 ]. In contrast to neutrophils that establish secretory vesicles by bulk membrane endocytosis, the uptake of SOD3 in macrophages appears to be mediated by the specific interaction with the cell surface receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which is highly expressed in macrophages [ 60 , 61 ]. Agonist-induced release of SOD3 from macrophages increases both the level of the enzyme in the extracellular environment and on the cell surface within hours [ 60 ].…”