Said Amel Ait Ali, Rizzo Chiara, Mambueni Hendrick Mambu, Costantino Félicie, Breban Maxime, Glatigny Simon
Université Paris Saclay, Université de Versailles St Quentin en Yvelines, Inserm, Infection et Inflammation, Montigny le Btx INSERM UMR1173, UFR Simone Veil, Versailles-Saint-Quentin University, Inserm, France.
INFLAMEX, Laboratoire d'Excellence, Université Paris Cité, Paris, France.
Arthritis Res Ther. 2025 Jun 13;27(1):124. doi: 10.1186/s13075-025-03586-9.
Spondyloarthritis (SpA) is a chronic inflammatory disorder with axial and peripheral manifestations. A strong association between HLA-B27 and SpA has been known for more than 50 years. Remarkably, HLA-B27 and human β2-microglubulin transgenic rats (B27 rat) develop manifestations recapitulating SpA, referred to as rat SpA. Antigen-presenting cells such as dendritic cells (DC) and CD4 T cells are mandatory to develop rat SpA. Serum levels of granulocyte macrophage-colony stimulating factor (GM-CSF), a key growth factor for DC generation and functions, are significantly increased during SpA. Conventional (c)DCs can be divided in two subsets implicated either in immune tolerance (cDC1) or in adaptive immune responses induction (cDC2). In this study, we aimed to determine the influence of GM-CSF on cDC subsets functions linked to T cell activation and differentiation, in the B27 rat model.
cDC subsets were isolated from spleens of B27 and nontransgenic (NTG) rats, primed with GM-CSF and tested for their ability to support CD4h T cell differentiation. RNA sequencing was performed on GM-CSF-primed cDC subsets.
GM-CSF-primed cDC2 from B27 rat were strong inducers of TNF-producing proinflammatory CD4 T cells. In contrast, whereas control cDC1 required GM-CSF to support T cell proliferation, HLA-B27 cDC1 primed with GM-CSF failed to do so. RNA sequencing analysis demonstrated that HLA-B27 expression promoted endoplasmic reticulum stress and unfolded protein response in both cDC subsets. In addition, HLA-B27 expression promoted inflammatory cytokine synthesis by cDC2 and a signature interfering with regulation of cell adhesion and activation in cDC1.
Altogether, our study reveals a dual role of GM-CSF during SpA. In one hand, GM-CSF promotes proinflammatory functions of cDC2. On the other hand, GM-CSF is required for cDC1 to induce T cell proliferation, and those functions are blunted by HLA-B27 expression.
脊柱关节炎（SpA）是一种具有中轴和外周表现的慢性炎症性疾病。HLA - B27与SpA之间的强关联已为人所知50多年。值得注意的是，HLA - B27和人β2 - 微球蛋白转基因大鼠（B27大鼠）会出现类似于SpA的表现，称为大鼠SpA。抗原呈递细胞如树突状细胞（DC）和CD4 T细胞是大鼠SpA发病所必需的。粒细胞巨噬细胞集落刺激因子（GM - CSF）是DC生成和功能的关键生长因子，其血清水平在SpA期间显著升高。传统（c）DC可分为两个亚群，分别参与免疫耐受（cDC1）或适应性免疫反应诱导（cDC2）。在本研究中，我们旨在确定GM - CSF对B27大鼠模型中与T细胞活化和分化相关的cDC亚群功能的影响。
从B27和非转基因（NTG）大鼠的脾脏中分离cDC亚群，用GM - CSF刺激，并检测它们支持CD4h T细胞分化的能力。对用GM - CSF刺激的cDC亚群进行RNA测序。
来自B27大鼠的经GM - CSF刺激的cDC2是产生TNF的促炎CD4 T细胞的强诱导剂。相比之下，虽然对照cDC1需要GM - CSF来支持T细胞增殖，但用GM - CSF刺激的HLA - B27 cDC1却不能。RNA测序分析表明，HLA - B27表达促进了两个cDC亚群的内质网应激和未折叠蛋白反应。此外，HLA - B27表达促进了cDC2的炎性细胞因子合成以及干扰cDC1中细胞黏附和活化调节的特征。
总之，我们的研究揭示了GM - CSF在SpA期间的双重作用。一方面，GM - CSF促进cDC2的促炎功能。另一方面，cDC1诱导T细胞增殖需要GM - CSF，而这些功能因HLA - B27表达而减弱。
