Abstract
Immune-mediated arthritis is an important chronic inflammatory disease of joints causing debilitating morbidity in affected patients. The mechanisms underlying immune-mediated arthritis have been intensively investigated, however the cellular and molecular factors contributing to the joint inflammation in different redox conditions have not been clearly elucidated. Previous research showed that phagocyte-produced reactive oxygen species (ROS) plays an anti-inflammatory role in K/BxN serum-transfer arthritis and NOX2-deficient mice tend to have more severe arthritis. Although many leukocytes play critical roles in the development of immune-mediated arthritis, the role of neutrophils, which are the main producers of ROS in inflammation, is still controversial. We hence assessed the immunomodulatory function of neutrophils from arthritic joints of NOX2-deficient and wild type mice in this study. We found more neutrophils accumulation in NOX2-deficient inflamed joints. RNA-sequencing and quantitative PCR revealed significantly increased expression of acute inflammation genes including IL1b, Cxcl2, Cxcl3, Cxcl10 and Mmp3 in activated neutrophils from the inflamed joints of NOX2-deficient mice. Moreover, gene set enrichment analysis (GSEA) showed enriched gene signatures in type I and II IFN responses, IL-6-JAK-STAT3 signaling pathway and TNF-α signaling pathway via NF-κB in NOX2-deficient neutrophils. In addition, we found that NOX2-deficient neutrophils expressed lower levels of PD-L1 and were less suppressive than WT neutrophils. Moreover, treatment of PD-L1-Fc decreased cytokine expression and ameliorated the severity of inflammatory arthritis. Our results suggest that NOX2-derived ROS is critical for regulating the function and gene expression in arthritic neutrophils. Both the strong pro-inflammatory and weakened anti-inflammatory functions of neutrophils due to abnormal redox regulation may be targets of treatment for immune-mediated arthritis.
Highlights
Immune-mediated inflammatory arthritis, including rheumatoid arthritis (RA) and juvenile idiopathic arthritis, is a family of chronic inflammatory diseases of joints characterized by tissue inflammation, synovial proliferation, autoantibody production and destruction of cartilage and bones [1]
In order to evaluate the role of NADPH oxidase 2 (NOX2)-produced reactive oxygen species (ROS) in inflammatory arthritis, K/BxN serum were injected into wild type (WT) and Neutrophil Cytosolic Factor 1 (Ncf1)-/- mice on day2 and day7 respectively
We found that the proportion of Ly6G+ cell was increased in the granulocyte population of Ncf1-/- inflamed joints when compared to WT control. (Figure 1D)
Summary
Immune-mediated inflammatory arthritis, including rheumatoid arthritis (RA) and juvenile idiopathic arthritis, is a family of chronic inflammatory diseases of joints characterized by tissue inflammation, synovial proliferation, autoantibody production and destruction of cartilage and bones [1]. Synovial inflammation occurs when leukocytes, including innate and adaptive immune cells, infiltrate into the joint compartment [3, 4]. Neutrophils in arthritis are active in the coordinating progress of inflammation by regulating the functions of other immune cells. Neutrophils are the first line of host defense against a wide range of infectious pathogens [7]. They are terminally differentiated, relatively short-lived leukocytes that can communicate with adaptive immune cells through cytokine secretion and cell-cell interaction [8,9,10]. Understanding the function and gene expression profile of neutrophils in immune-mediated arthritis is important for developing therapeutic interventions
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