免疫引起之關節炎是一種慢性發炎性關節疾病。雖然此疾病機轉已被廣泛地研究，但是在不同的氧化還原狀態下的細胞與分子如何造成免疫性關節炎這部分還尚未研究清楚。先前的研究指出菸醯胺腺嘌呤二磷酸氧化酶 (NOX2)所產生的活性氧分子(ROS)在K/BxN血清引起的關節炎中具有抗發炎的功能，並且NOX2缺陷的小鼠會產生更加嚴重的免疫性關節炎。雖然很多種白血球在免疫性關節炎的發展中都扮演了角色，但是主要表現NOX2的嗜中性球的角色還尚未釐清。所以，我們想要研究NOX2缺陷的嗜中性球以及正常的嗜中性球在免疫性關節炎中的免疫調節功能。初步的研究結果發現在NOX2缺陷的小鼠關節以及類風溼性關節炎的關節液中有比較多的嗜中性球浸潤和累積。同時我們也發現了在類風溼性關節炎之關節液中，氧化壓力標記的表現量比較低，IL-6則是有較高的表現量。接著，在使用RNA定序技術分析抗體活化之NOX2缺陷嗜中性球的基因表現之後，我們發現急性發炎性基因包括: IL1b、Cxcl2、Cxcl3、Cxcl10和Mmp3 等等的基因表現都上升。再進一步地使用gene set enrichment analysis (GSEA) 分析RNA定序的結果後發現，第一和第二型干擾素反應基因群、介白素6-JAK-STAT3訊息傳遞路徑基因群以及腫瘤壞死因子經由NF-B的訊息傳遞路徑基因群的表現量都在NOX2缺陷的嗜中性球中提高了。同時，我們發現NOX2缺陷嗜中性球抑制正常T細胞增生的功能較弱，其免疫檢查點的表現量也較少。在加強了免疫檢查點在NOX2缺陷的小鼠表現量之後，細胞激素的表現以及關節炎的嚴重性都降低了。我們也進一步地測量類風濕性關節炎之關節液中嗜中性球的免疫抑制功能，結果發現其功能是比周邊血液嗜中性球較差。總而言之，活性氧分子，特別是由NOX 2所產生的，在免疫引起的關節炎中具有極為重要的免疫調節功能，所以調節氧化還原狀態是具有潛力的目標可用於治療免疫引起的關節炎。

Immune-mediated arthritis is an important 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 NADPH oxidase 2 (NOX2)-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 and synovial fluid of RA patients. The expression of oxidative stress markers is lower, whereas IL-6 expression is higher in synovial fluid of RA patients. 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 signalling pathway and TNF-a signalling pathway via NF-kB 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. Additionally, treatment of PD-L1-Fc decreased cytokine expression and ameliorated the severity of inflammatory arthritis. Furthermore, we found that neutrophils from synovial fluid of RA patient is less suppressive than peripheral neutrophils. Our results suggest that NOX2-derived ROS is critical for regulating the function and gene expression in arthritic neutrophils. Abnormal redox regulation may be targets of treatment for immune-mediated arthritis.

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