The Meakins-Christie Laboratories, Research Institute of the McGill University Heath Centre, Montréal, QC, Canada.
Department of Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.
Front Immunol. 2024 Oct 18;15:1452788. doi: 10.3389/fimmu.2024.1452788. eCollection 2024.
Severe COVID-19 is associated with neutrophilic inflammation and immunothrombosis. Several members of the IL-17 cytokine family have been associated with neutrophilic inflammation and activation of the endothelium. Therefore, we investigated whether these cytokines were associated with COVID-19.
We investigated the association between COVID-19 and circulating plasma levels of IL-17 cytokine family members in participants to the Biobanque québécoise de la COVID-19 (BQC19), a prospective observational cohort and an independent cohort from Western University (London, Ontario). We measured the in vitro impact of IL-17F on intercellular adhesion molecule 1 (ICAM-1) cell surface expression and neutrophil adhesion on endothelial cells in culture. The contribution of two Mitogen Activated Protein Kinase (MAPK) pathways was determined using small molecule inhibitors PD184352 (a MKK1/MKK2 inhibitor) and BIRB0796 (a p38 MAPK inhibitor).
We found increased IL-17D and IL-17F plasma levels when comparing SARS-CoV-2-positive vs negative hospitalized participants. Moreover, increased plasma levels of IL-17D, IL-17E and IL-17F were noted when comparing severe versus mild COVID-19. IL-17F, but not IL-17A, was significantly elevated in people with COVID-19 compared to healthy controls and with more severe disease. In vitro work on endothelial cells treated with IL-17F for 24h showed an increase cell surface expression of ICAM-1 accompanied by neutrophil adhesion. The introduction of two MAPK inhibitors significantly reduced the binding of neutrophils while also reducing ICAM-1 expression at the surface level of endothelial cells, but not its intracellular expression.
Overall, these results have identified an association between two cytokines of the IL-17 family (IL-17D and IL-17F) with COVID-19 and disease severity. Considering that IL-17F stimulation promotes neutrophil adhesion to the endothelium in a MAPK-dependent manner, it is attractive to speculate that this pathway may contribute to pathogenic immunothrombosis in concert with other molecular effectors.
严重的 COVID-19 与中性粒细胞炎症和免疫血栓形成有关。白细胞介素-17 细胞因子家族的几个成员与中性粒细胞炎症和内皮细胞的激活有关。因此，我们研究了这些细胞因子是否与 COVID-19 有关。
我们研究了 COVID-19 参与者的循环血浆中白细胞介素-17 细胞因子家族成员与 COVID-19 的关系，参与者来自魁北克 COVID-19 生物银行（BQC19）的一项前瞻性观察队列和安大略省西部大学的一个独立队列。我们测量了白细胞介素-17F 在体外对细胞间粘附分子 1（ICAM-1）细胞表面表达和中性粒细胞在内皮细胞上的粘附的影响。使用小分子抑制剂 PD184352（MKK1/MKK2 抑制剂）和 BIRB0796（p38 MAPK 抑制剂）确定两条丝裂原激活蛋白激酶（MAPK）途径的贡献。
与 SARS-CoV-2 阳性住院患者相比，我们发现白细胞介素-17D 和白细胞介素-17F 的血浆水平升高。此外，当比较严重的 COVID-19 与轻度 COVID-19 时，发现白细胞介素-17D、白细胞介素-17E 和白细胞介素-17F 的血浆水平升高。与健康对照组和疾病更严重的人相比，IL-17F（而非 IL-17A）在 COVID-19 患者中显著升高。在体外，用白细胞介素-17F 处理内皮细胞 24 小时后，细胞表面 ICAM-1 的表达增加，同时伴有中性粒细胞的粘附。两种 MAPK 抑制剂的引入显著减少了中性粒细胞的结合，同时也减少了内皮细胞表面 ICAM-1 的表达，但不减少其细胞内表达。
总的来说，这些结果表明白细胞介素-17 家族的两种细胞因子（白细胞介素-17D 和白细胞介素-17F）与 COVID-19 和疾病严重程度有关。考虑到白细胞介素-17F 刺激以 MAPK 依赖的方式促进中性粒细胞与内皮细胞的粘附，推测该途径可能与其他分子效应物一起导致致病免疫血栓形成。
