Neutrophil infiltration is a hallmark of lung inflammation during respiratory viral infections, but the origin of these cells is a subject of debate. A study led by Professor Xuetao Cao’s team from the Chinese Academy of Medical Sciences used a golden hamster model of SARS-CoV-2 infection to uncover a dynamic spleen-to-lung neutrophil axis that operates during antiviral defense. Their discovery is immunity and inflammation Diary of March 11, 2026. team Integrating single-cell RNA velocity analysis and spatial transcriptome deconvolution to track neutrophil dynamics across time and tissues. What emerged was a clear picture of the crosstalk between organs. At the peak of the antiviral response, spleen-derived neutrophils migrate to the lungs, replenish the local pool at different stages of differentiation, and actively participate in the innate immune defense.
The research began with a detailed dynamic analysis of lung immune cells. Single-cell RNA velocity profiling of lung tissue at day 7 postinfection revealed a unidirectional differentiation trajectory within the neutrophil compartment from proliferative subsets through immature and mature stages to fully activated cells. Remarkably, the proliferation and activation phases were temporally and transcriptionally distinct, suggesting that local proliferation alone cannot explain the enormous scale of neutrophil accumulation.
Between days 5 and 7 postinfection, a marked increase in the number of neutrophils was observed in the spleen, which coincided precisely with the peak of lung infiltration. This temporal synchrony led to comparative transcriptome analysis of neutrophil subsets in both organs. The results were amazing. Neutrophils in the spleen and lung were divided into the same three major subsets (proliferative, nonactivated, and activated), and the gene expression profiles within each subset were very similar. This transcriptional similarity strongly suggested that neutrophils accumulating in the spleen during this period were destined for the lungs.
To directly test whether splenocytes seed the lung, the team utilized spatial transcriptomics data from lung tissue and used the single-cell dataset as a reference for deconvolution analysis with the Redeconve algorithm. This approach allowed precise localization of cell subsets of different origin within lung structures. Among all immune cell types examined, only neutrophils showed a substantial contribution from the spleen. By days 5 to 7 postinfection, the proportion of spleen-derived neutrophils in the lungs matched or exceeded the proportion of locally derived cells. In contrast, other immune populations remained primarily lung-derived, with minimal input from the spleen.
Splenic neutrophil influx followed a temporally coordinated pattern. On day 5, early differentiated proliferating neutrophils from the spleen were concentrated in the lungs. By day 7, the predominant subset has shifted to immature and mature/mildly activated splenic neutrophils, indicating a continuous supply chain from progenitor to effector cells.
Directional migration of immune cells relies on precise chemokine receptor interactions. The research team identified the molecular basis for this transport from the spleen to the lungs. At days 5 to 7 postinfection, lung tissue showed peak expression of multiple neutrophil-attracting chemokines, including: Cxcl5, Cxcl12and Ccl11. These chemokines are produced by specific cell populations in the lungs (epithelial cells, macrophages, and fibroblasts), each contributing a different signal.
At the same time, splenic neutrophils at different stages of differentiation showed different chemokine receptor expression. Preferentially expressed in immature neutrophils Cxcr4receptor for Cxcl12whereas mature neutrophils were upregulated Cxcr2, Ccr1and Ccr3combine Cxcl5, Ccl11, and other chemokines. This match between receptors on migrating cells and ligands produced in the lung creates a chemokine code that guides the precise stage-specific recruitment of splenic neutrophils to the inflamed organ.
”This study fundamentally modifies our understanding of neutrophil dynamics during respiratory viral infections.“By integrating single-cell and spatial multiomics, the research team demonstrated that the spleen acts as an extramedullary hub for neutrophil recruitment, supplying a continuous flow of cells to the lungs at different stages of differentiation to meet the demands of antiviral defenses,” Professor Cao noted. network.
”Identification of the spleen-to-lung neutrophil axis and chemokines–The receptor pair that governs it opens new avenues for therapeutic intervention.‘, the authors emphasized. Targeting this axis may provide a means to modulate immune cell recruitment and activity for inflammatory lung diseases caused by exaggerated or dysregulated neutrophil responses, including severe viral pneumonia. This study provides a new theoretical framework for understanding immune coordination between organs and highlights potential diagnostic and therapeutic targets for pulmonary infections.
sauce:
Chinese Academy of Medical Sciences immunity and inflammation
Reference magazines:
DOI: 10.1007/s44466-026-00030-8
