Identification of myeloid cells in the human enthesis as the main source of local IL-23 production
Identification of myeloid cells in the human enthesis as the main source of local IL-23 production
复制标题
DOI：
10.1136/annrheumdis-2018-214944
复制
发表时间：
2019-07-01
影响因子：
27.4
通讯作者：
McGonagle, Dennis G.
中科院分区：
文献类型：
--
作者：
Bridgewood, Charlie;Watad, Abdulla;McGonagle, Dennis G.
目的研究正常人脊髓末端是否含有能产生肿瘤坏死因子(TNF)和白介素23(IL-23)等关键致炎细胞因子的髓系细胞群，并确定PDE4抑制剂能否改变这些细胞群。方法采用免疫组织化学(IHC)法检测正常人末端软组织(ST)和邻近末端周围骨(PEB)(n=15)，消化髓系细胞表型，分选并用不同佐剂(脂多糖和甘露聚糖)刺激。分析脊椎关节病疾病相关介质(IL-23全蛋白、肿瘤坏死因子、IL-1β和CCL20)的诱生作用。结果从ST段及邻近PEB中分离到一株髓系细胞(CD45+HLADR+CD14+CD11c+)，命名为CD14+髓系细胞，组织定位经CD14+IHC证实。CD14组分含有CD123+HLADR+CD11c-细胞群(浆细胞样树突状细胞)。CD14+细胞主要分泌IL-23、IL-1β、肿瘤坏死因子和CCL20。PDE4I和其他升高cAMP的药物(组胺和8-溴-cAMP)可下调CD14+细胞产生的IL-23和肿瘤坏死因子。Entheseal CD14+细胞的基因表达谱与匹配血液中相应的CD14+细胞相似，但CCR2基因的表达显著降低。结论人类胚胎发育过程中含有CD14+髓系细胞，可产生大部分可诱导的IL-23、IL-1β、肿瘤坏死因子和CCL20。该人群的基因表达谱与匹配的血液CD14+人群相似。
Objective We investigated whether the normal human spinal enthesis contained resident myeloid cell populations, capable of producing pivotal proinflammatory cytokines including tumour necrosis factor (TNF) and interleukin (IL)-23 and determined whether these could be modified by PDE4 inhibition.Methods Normal human enthesis soft tissue (ST) and adjacent perientheseal bone (PEB) (n=15) were evaluated using immunohistochemistry (IHC), digested for myeloid cell phenotyping, sorted and stimulated with different adjuvants (lipopolysaccharide and mannan). Stimulated enthesis fractions were analysed for inducible production of spondyloarthropathy disease-relevant mediators (IL-23 full protein, TNF, IL-1 beta and CCL20). Myeloid populations were also compared with matched blood populations for further mRNA analysis and the effect of PDE4 inhibition was assessed.Results A myeloid cell population (CD45+ HLADR+ CD14+ CD11c+) phenotype was isolated from both the ST and adjacent PEB and termed 'CD14+ myeloid cells' with tissue localisation confirmed by CD14+ IHC. The CD14-fraction contained a CD123+ HLADR+ CD11c-cell population (plasmacytoid dendritic cells). The CD14+ population was the dominant entheseal producer of IL-23, IL-1 beta, TNF and CCL20. IL-23 and TNF from the CD14+ population could be downregulated by a PDE4I and other agents (histamine and 8-Bromo-cAMP) which elevate cAMP. Entheseal CD14+ cells had a broadly similar gene expression profile to the corresponding CD14+ population from matched blood but showed significantly lower CCR2 gene expression.Conclusions The human enthesis contains a CD14+ myeloid population that produces most of the inducible IL-23, IL-1 beta, TNF and CCL20. This population has similar gene expression profile to the matched blood CD14+ population.