Respiratory research · 2026
The crucial role of RIG-I in upregulating neutrophil CXCR2 expression through the MAPK signaling pathway in viral pneumonia.
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Wang Yuxin, Shi Qi, Pan Yaxin, Sun Xiaoyu, Wang Huayang, Zhang Yi
Аннотация
BACKGROUND: Dysregulated neutrophilic inflammation is a hallmark of severe COVID-19, but the mechanisms driving human peripheral neutrophils (HPNs) recruitment remain incompletely defined. C-X-C motif chemokine receptor 2 (CXCR2), a key chemokine receptor on HPNs, is essential for HPNs recruitment during viral pneumonia. However, the role and underlying regulatory mechanisms of CXCR2 on HPNs during viral pneumonia remain unclear.
METHODS: We enrolled 66 COVID-19 patients (30 mild, 33 severe) and 31 healthy controls (HCs). The content of HPNs and the CXCR2 expression on the HPNs were tracked using flow cytometry, RT-qPCR, and ELISA. Transcriptomic sequencing identified differential pathways in the patients. In vitro, HPNs and lung epithelial cells (A549, BEAS-2B) were stimulated with the viral mimic poly(I: C) and treated with pathway inhibitors (CXCR2: SB225002; RIG-I: BX795; MEK: PD98059). In vivo, a poly(I: C)-induced acute lung injury mouse model was used to confirm the roles of RIG-I and CXCR2 in lung injury progression.
RESULTS: Severe patients exhibited a higher HPN percentage and CXCR2 expression. Higher CXCR2 expression was correlated with poor prognosis and elevated inflammatory cytokines (TNF-α, IL-6, and IL-8). In vitro, poly(I: C) triggered lung epithelial cells to produce CXCR2 ligands (CXCL1/2/8), increase pro-inflammatory factors, and promote the HPNs migration to epithelial cells. However, CXCR2 antagonists could reduce the HPNs recruitment and inflammatory factors in HPNs supernatants. Mechanistically, poly(I: C)-mediated activation of intracellular RIG-I upregulated CXCR2 expression on HPNs via the MAPK pathway. In vivo, inhibiting CXCR2, RIG-I, or depleting neutrophils significantly alleviated poly(I: C)-induced inflammatory lung injury, inflammation, and neutrophil infiltration.
CONCLUSION: Our study identifies the RIG-I-MAPK-CXCR2 axis as a novel pathogenic signaling cascade that drives dysregulated neutrophilic inflammation in COVID-19, providing a basis for novel therapeutic strategies against respiratory viral infections.
METHODS: We enrolled 66 COVID-19 patients (30 mild, 33 severe) and 31 healthy controls (HCs). The content of HPNs and the CXCR2 expression on the HPNs were tracked using flow cytometry, RT-qPCR, and ELISA. Transcriptomic sequencing identified differential pathways in the patients. In vitro, HPNs and lung epithelial cells (A549, BEAS-2B) were stimulated with the viral mimic poly(I: C) and treated with pathway inhibitors (CXCR2: SB225002; RIG-I: BX795; MEK: PD98059). In vivo, a poly(I: C)-induced acute lung injury mouse model was used to confirm the roles of RIG-I and CXCR2 in lung injury progression.
RESULTS: Severe patients exhibited a higher HPN percentage and CXCR2 expression. Higher CXCR2 expression was correlated with poor prognosis and elevated inflammatory cytokines (TNF-α, IL-6, and IL-8). In vitro, poly(I: C) triggered lung epithelial cells to produce CXCR2 ligands (CXCL1/2/8), increase pro-inflammatory factors, and promote the HPNs migration to epithelial cells. However, CXCR2 antagonists could reduce the HPNs recruitment and inflammatory factors in HPNs supernatants. Mechanistically, poly(I: C)-mediated activation of intracellular RIG-I upregulated CXCR2 expression on HPNs via the MAPK pathway. In vivo, inhibiting CXCR2, RIG-I, or depleting neutrophils significantly alleviated poly(I: C)-induced inflammatory lung injury, inflammation, and neutrophil infiltration.
CONCLUSION: Our study identifies the RIG-I-MAPK-CXCR2 axis as a novel pathogenic signaling cascade that drives dysregulated neutrophilic inflammation in COVID-19, providing a basis for novel therapeutic strategies against respiratory viral infections.