Lee Ming-Chin, McCubbin James A, Christensen Anne D, Poole Daniel P, Rajasekhar Pradeep, Lieu TinaMarie, Bunnett Nigel W, Garcia-Caraballo Sonia, Erickson Andelain, Brierley Stuart M, Saleh Reem, Achuthan Adrian, Fleetwood Andrew J, Anderson Robin L, Hamilton John A, Cook Andrew D
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia.
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
J Immunol. 2017 May 1;198(9):3565-3575. doi: 10.4049/jimmunol.1602127. Epub 2017 Mar 20.
G-CSF or CSF-3, originally defined as a regulator of granulocyte lineage development via its cell surface receptor (G-CSFR), can play a role in inflammation, and hence in many pathologies, due to its effects on mature lineage populations. Given this, and because pain is an extremely important arthritis symptom, the efficacy of an anti-G-CSFR mAb for arthritic pain and disease was compared with that of a neutrophil-depleting mAb, anti-Ly6G, in both adaptive and innate immune-mediated murine models. Pain and disease were ameliorated in Ag-induced arthritis, zymosan-induced arthritis, and methylated BSA/IL-1 arthritis by both prophylactic and therapeutic anti-G-CSFR mAb treatment, whereas only prophylactic anti-Ly6G mAb treatment was effective. Efficacy for pain and disease correlated with reduced joint neutrophil numbers and, importantly, benefits were noted without necessarily the concomitant reduction in circulating neutrophils. Anti-G-CSFR mAb also suppressed zymosan-induced inflammatory pain. A new G-CSF-driven (methylated BSA/G-CSF) arthritis model was established enabling us to demonstrate that pain was blocked by a cyclooxygenase-2 inhibitor, suggesting an indirect effect on neurons. Correspondingly, dorsal root ganglion neurons cultured in G-CSF failed to respond to G-CSF in vitro, and gene expression could not be detected in dorsal root ganglion neurons by single-cell RT-PCR. These data suggest that G-CSFR/G-CSF targeting may be a safe therapeutic strategy for arthritis and other inflammatory conditions, particularly those in which pain is important, as well as for inflammatory pain per se.
粒细胞集落刺激因子（G-CSF）或CSF-3最初被定义为通过其细胞表面受体（G-CSFR）调节粒细胞谱系发育的因子，由于其对成熟谱系群体的影响，它可在炎症中发挥作用，进而在许多病理过程中发挥作用。鉴于此，并且由于疼痛是关节炎的一种极其重要的症状，在适应性和先天性免疫介导的小鼠模型中，比较了抗G-CSFR单克隆抗体与中性粒细胞清除单克隆抗体抗Ly6G对关节炎疼痛和疾病的疗效。预防性和治疗性抗G-CSFR单克隆抗体治疗可改善抗原诱导的关节炎、酵母聚糖诱导的关节炎和甲基化牛血清白蛋白/白细胞介素-1诱导的关节炎中的疼痛和疾病，而只有预防性抗Ly6G单克隆抗体治疗有效。疼痛和疾病的疗效与关节中性粒细胞数量减少相关，重要的是，在循环中性粒细胞不一定减少的情况下也观察到了益处。抗G-CSFR单克隆抗体还可抑制酵母聚糖诱导的炎性疼痛。建立了一种新的G-CSF驱动（甲基化牛血清白蛋白/G-CSF）关节炎模型，使我们能够证明环氧合酶-2抑制剂可阻断疼痛，这表明对神经元有间接影响。相应地，在G-CSF中培养的背根神经节神经元在体外对G-CSF无反应，并且通过单细胞逆转录聚合酶链反应在背根神经节神经元中未检测到基因表达。这些数据表明，靶向G-CSFR/G-CSF可能是治疗关节炎和其他炎症性疾病的安全策略，特别是那些疼痛很重要的疾病，以及炎性疼痛本身。
