Using publicly available genetic data, this research undertook a comprehensive examination of the causal connection between sepsis and 731 immune cell traits through MR. This pioneering investigation represents the first exploration of the link between sepsis and various immune cell phenotypes using this innovative approach. Sepsis-related immune paralysis is primarily driven by dysfunctional immune cells, leading to immunosuppression and a significant cause of mortality23. Therefore, this study employed Mendelian randomization and an extensive analysis of single-cell transcriptomes to investigate the characteristics and interplay of immune cells in sepsis, providing unique insights into its treatment.
This study marks a significant achievement as it unveils the beneficial impact of HLA DR+ natural killer (NK) cells against sepsis. NK cells serve as a vital component of the innate immune system and play a crucial role in mediating the natural immune response. Unlike the reliance on antibodies and complement, NK cells directly eliminate target cells, such as infected, foreign, stressed, or transformed cells, thereby ensuring the protection of the host. Proinflammatory cytokines, namely interferon-γ and granulocyte macrophage colony-stimulating factor, are primarily produced by NK cells, and they play an essential role in combatting infections24. However, it is worth noting that their rapid response may also give rise to excessive and harmful inflammation25. In humans, NK cells express surface markers involved in differentiation, migration, and cytolysis, and different subsets of NK cells have varying immune functions26. Therefore, detection of changes in NK cell subsets is crucial for a more comprehensive understanding of NK cell functions in sepsis. The presence of HLA-DR, a critical antigen located on the surface of monocytes, assumes a significant role in identifying foreign antigens during the activation of specific T cells for immune response. Numerous clinical and experimental animal studies have observed a decrease in NK cells during sepsis, and it is believed that NK cells expressing HLA-DR are actively proliferating during inflammatory disorders. This explains why these cells are present in high numbers in peripheral blood27,28. Notably, HLA DR+ NK cells possess phenotypic characteristics of both NK cells and dendritic cells, allowing them to produce pro-inflammatory cytokines29. The expression of HLA-DR on NK cells is an indicator of cell activation. HLA DR+ NK cells are associated with a higher level of IFN-γ production, and IFN-γ stimulates the expression of HLA-DR on NK cells30. Moreover, these cells have the ability to uptake and direct CD4 + and CD8 + T cells towards specific antigens, thereby inducing their activation and proliferation 29,31. Additionally, HLA-DR + NK cells play a regulatory role in both innate and adaptive immune responses, making them valuable contributors to the innate immune system32. Exploring immunotherapy utilizing NK cells holds promising potential for the treatment of various cancers33. In our study, a higher expression level of HLA-DR on NK cells is associated with a lower risk of sepsis. The discovery of the protective effect of HLA DR+ NK cells in sepsis not only adds new dimensions to our understanding but also paves the way for potential immunotherapy strategies in sepsis.
In order to gain further insights into the characteristics of immune cell subtypes in sepsis, we conducted an analysis on single-cell transcriptome data. Our findings revealed a noticeable increase in the subpopulations of neutrophils expressing S100A8 and S100A9 in sepsis patients, indicating their crucial role in the development of sepsis34. S100A8 and S100A9 are pro-inflammatory molecules that are released by myeloid cells in various acute and chronic inflammatory conditions. These molecules exist as inactive heterodimers known as S100A8/A9 or calprotectins within neutrophils, and are rapidly released upon activation. It is believed that they contribute to the recruitment of neutrophils and the progression of the disease35,36. Moreover, the overexpression of S100A8 and S100A9 accelerates the release of additional cytokines from neutrophils and macrophages, triggering a vicious cycle that exacerbates the inflammatory response37. These proteins also serve as molecular markers associated with inflammation38–40. To gain further insight, we conducted pathway enrichment analysis on the differentially expressed genes within the S100A8 + S100A9 + neutrophil subpopulation in both healthy individuals and sepsis patients. The results revealed a significant enrichment of the type I interferon signaling pathway, providing additional evidence of the strong link between this particular neutrophil subpopulation and the excessive inflammatory response observed in sepsis41. Based on our findings, it is evident that the significantly elevated level of the S100A8 + S100A9 + neutrophil subpopulation can serve as a crucial marker for assessing the severity of inflammation and predicting the prognosis of sepsis. This understanding could potentially contribute to improved diagnostic and therapeutic strategies for sepsis.
It has been observed through the analysis of the ratio between natural killer cells (NK cells) and T cells in sepsis patients that the T cell ratio is significantly lower compared to healthy individuals. This finding suggests the presence of immunosuppression in sepsis patients. At the onset of sepsis, patients exhibit an extreme immune response, followed by persistent immunosuppression in later stages. Ultimately, this sepsis-induced immunosuppression can lead to fatal outcomes. The immunocompromised state in the late stages of sepsis is attributed to the upregulation of myelosuppressive cells and reduced immune activity in lymphocytes, known as lymphocyte hypofunction42. T cell responses, specifically those mediated by CD4 and CD8 αβ T cells, are impaired in sepsis patients43. Additionally, severe and transient lymphopenia induced by sepsis plays a crucial role in weakening T cell immunity. The quantity of T cells during infection is closely linked to the initiation of inflammatory responses. Research on tumors and inflammation has demonstrated that a decrease in T cells can hinder immune function in the body44–47. Therefore, promoting the restoration of T cell numbers and function in sepsis holds great potential as an effective strategy to reduce sepsis mortality and improve prognosis.
A Mendelian randomization trial has established that natural killer cells expressing HLA-DR possess a protective effect against sepsis. Further analysis of the transcriptome of individual immune cells has revealed specific changes in subpopulations of neutrophils, characterized by the expression of S100A8 + and S100A9+, as well as a notable decrease in the proportion of T cells. These alterations may serve as potential indicators for the development and prognosis of sepsis. Therefore, it can be deduced that sepsis is a multifaceted disorder characterized by an immune system dysfunction, where the involvement of immune cells is pivotal in both its onset and severity. Nevertheless, it is crucial to acknowledge that this study did not investigate the distinct immunomodulatory and targeting functions of various subtypes of NK cells, T cells, and neutrophils in the context of sepsis, thereby highlighting the necessity for additional scientific investigation. By focusing on immune cells as a treatment strategy for sepsis, it may be possible to restore immune balance and improve patient outcomes.