Abstract
BackgroundAlthough the immune function of neutrophils in sepsis has been well described, the heterogeneity of neutrophils remains unclear during the process of sepsis.MethodsIn this study, we used a mouse CLP model to simulate the clinical scenario of patients with sepsis, neutrophil infiltration, abnormal distribution and dysfunction was analyzed. LPS was used to stimulate neutrophils in vitro to simulate sepsis; single-cell gene sequencing technology was used to explore the immunological typing. To explore the immunological function of immunosuppressive neutrophils, PD-L1 knockout neutrophils were cocultured with lymphocytes from wild-type mice.ResultsWe found that neutrophils presented variant dysfunction at the late stage of sepsis, including inhibition of apoptosis, seriously damaged chemotaxis and extensive infiltration into the tissues. Single-cell RNA sequencing revealed that multiple subclusters of neutrophils were differentiated after LPS stimulation. The two-dimensional spatial distribution analysis showed that Foxp3+ T cells were much closer to Ly-6G than the CD4+ and CD8+ cells, indicating that infiltrated neutrophils may play immunomodulatory effect on surrounding T-regs. Further observations showed that LPS mediates PD-L1 over expression through p38α-MSK1/-MK2 pathway in neutrophils. The subsets of highly expressed PD-L1 exert immunosuppressive effect under direct contact mode, including inhibition of T cell activation and induction of T cell apoptosis and trans-differentiation.ConclusionsTaken together, our data identify a previously unknown immunosuppressive subset of neutrophils as inhibitory neutrophil in order to more accurately describe the phenotype and characteristics of these cells in sepsis.
Highlights
Sepsis is a condition with high mortality and morbidity rates and is severe in bacterial infections, epidemic virus infections, especially in intensive care patients [2]
Neutrophil infiltration, abnormal distribution and dysfunction are associated with the progression of sepsis To investigate the relationship between neutrophil infiltration and the mortality rate of mice with sepsis, we used a mouse Cecal ligation and puncture (CLP) model to simulate the clinical scenario of patients with sepsis
When PD-L1−/− neutrophils were cocultured with T lymphocytes (Fig. 7e), the neutrophil-mediated increase in T-regs was diminished. These results suggest that the modulatory function of neutrophils on lymphocyte transdifferentiation is dependent on neutrophil expression of PD-L1 and direct contact with the neutrophil
Summary
Sepsis is a condition with high mortality and morbidity rates and is severe in bacterial infections, epidemic virus infections (such as severe COVID-19 [1] infection), especially in intensive care patients [2]. Many factors, such as genetics, age, sex, ethnicity, the number of dysfunctional organs, immune status and therapeutic efficacy, have been linked to survival outcomes in severe sepsis. Dysfunction of the immune system gradually appears with the progression of the disease and causes immunosuppression. The immune function of neutrophils in sepsis has been well described, the heterogeneity of neutrophils remains unclear during the process of sepsis
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