Zheng Jian, Dhakal Hima, Qing Enya, Shrestha Rejeena, Geller Anne E, Morrissey Samantha M, Saxena Divyasha, Hu Xiaoling, Li Hong, Li Haiyan, Wilhelmsen Kevin, Wendt Linder H, Klumpp Klaus, Hume Patrick S, Janssen William J, Brody Rachel, Palmer Kenneth E, Uriarte Silvia M, Ten Eyck Patrick, Meyerholz David K, Merchant Michael L, McLeish Kenneth, Gallagher Tom, Huang Jiapeng, Yan Jun, Perlman Stanley
Department of Microbiology and Immunology and.
Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA.
J Clin Invest. 2025 Jan 7;135(4):e188222. doi: 10.1172/JCI188222.
Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells. CXCL12 levels were negatively correlated with LDN numbers in longitudinal analyses of patient blood samples. CXCL12 blockade in SARS-CoV-2-infected mice increased blood/lung neutrophil numbers, thereby accelerating disease progression without changing lung virus titers. The exaggerated mortality caused by CXCL12 blockade could be reversed by neutrophil depletion. In addition, blocking interactions between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) reduced CXCL12 levels, suggesting a signal transduction from virus-mediated ACE2 ligation to increased CXCL12 secretion. Collectively, these results demonstrate a previously unappreciated role of CXCL12 in diminishing neutrophilia, including low-density neutrophilia, and its deleterious effects in SARS-CoV-2 infections. The results also support the involvement of SARS-CoV-2-endothelial cell interactions in viral pathogenesis.
中性粒细胞，尤其是低密度中性粒细胞（LDNs），被认为与新冠肺炎的严重程度有关。在此，我们发现患者和小鼠在感染新冠病毒后可急性检测到嗜中性粒细胞增多，甚至在数月后仍存在，而中性粒细胞耗竭可降低小鼠的疾病严重程度。感染小鼠嗜中性粒细胞增多和严重疾病的一个关键因素可追溯到骨髓细胞，出乎意料的是，还有内皮细胞分泌的趋化因子CXCL12。在对患者血液样本的纵向分析中，CXCL12水平与LDN数量呈负相关。在感染新冠病毒的小鼠中阻断CXCL12会增加血液/肺部中性粒细胞数量，从而加速疾病进展，而不改变肺部病毒滴度。CXCL12阻断导致的过高死亡率可通过中性粒细胞耗竭来逆转。此外，阻断新冠病毒与血管紧张素转换酶2（ACE2）之间的相互作用可降低CXCL12水平，这表明存在从病毒介导的ACE2连接到CXCL12分泌增加的信号转导。总的来说，这些结果证明了CXCL12在减轻嗜中性粒细胞增多（包括低密度嗜中性粒细胞增多）及其在新冠病毒感染中的有害作用方面具有以前未被认识到的作用。这些结果还支持了新冠病毒与内皮细胞相互作用参与病毒发病机制。
