In recent years, there has been an increased awareness of sepsis among clinicians due to ongoing campaigns and research. This has led to improvements in measures for the prevention, diagnosis and management of sepsis [26]. However, despite the efforts to improve survival rates, sepsis remains a leading cause of death for hospitalized patients in ICU[27].The high mortality rate can be attributed to multiple comorbidities and underlying disease that make early diagnosis challenging. Therefore, early diagnosis and treatment are critical to improving patient outcomes[3, 28]. By improving the recognition and diagnosis of sepsis and exploring its pathogenesis, we can make significant strides in improving patient prognosis.
Nowadays, significant progress has been made in the study of miRNA functions and their potential impact on various diseases. The primary function of miRNAs in the human body is to regulate gene expression by mediating mRNA degradation and regulating transcription and translation through both canonical and non-canonical mechanisms[29]. And a growing number of studies suggested that abnormal miRNA expression is associated with sepsis[30, 31]. For example, Yu et al. have reported miR-146a-5p exacerbated sepsis by activating DCs and promoting glycolysis through targeting ATG7[32]. In addition, Zhang et al. have showed that the inhibition of miR-29a-3p expression in animal models reduced sepsis-induced cardiac dysfunction and inflammatory response[33]. Through comparative analysis in the blood of sepsis patients and healthy individuals, hsa-miR-34b-3p, hsa-miR-3663-3p and hsa-miR-4446-5p were identified as key roles in sepsis. Subsequently, we utilized the miRNA-mRNA databases to predict the target genes of these miRNAs and overlapped them with sepsis-related gene sets, ultimately yielding a list of putative target genes including ADRB2, GHR, PPARGC1A and GRIN2A.
ADRB2 has been linked to mortality and organ dysfunction in septic shock[34]. However, the mechanisms by which ADRB2 regulates sepsis remain unclear. In this study, we observed lower expression of ADRB2 in sepsis patients compared with healthy individuals, and the ROC curve suggested that ADRB2 has good diagnostic value for sepsis. Analysis of the KEGG pathway based on DEGs suggested that ADRB2 may be involved in metabolism, immunodeficiency, and viral infection. Furthermore, we also noticed that ADRB2 expression was positively correlated with T cell co-inhibition and negatively correlated with DCs infiltration.
DCs are heterogeneous antigen-presenting cells that play critical roles in immune defense [35–37]. During infection, DCs present antigens to naïve CD8 T cells, leading to their activation and rapid proliferation to eradicate the infection[38]. It has been reported that NKT cells can initiate specific innate cytokine responses to enhance NK cells proliferation, IFN-γ production, and killing capacity of virus-infected cells during viral infection[39, 40]. In addition, previous studies also reported that the mammalian nervous system can directly control the immune system through norepinephrine (NE), and NE mediates immunosuppression exclusively through ADRB2 [41]. Therefore, we speculated that ADRB2 was activated in immune cells such as T lymphocytes after pathogen infection, suppressing their innate immune function and exacerbating sepsis.
Furthermore, the PPI result suggested an interaction between ADRB2 and SPTB, which play a role in the stability of erythrocyte membranes[42]. Erythrocytes carry a variety of signaling molecules, including adrenergic receptors[43]. Pathogens may invade erythrocytes during infection, leading to membrane structure changes and eryptosis, which causes erythrocyte death[44]. Structural changes in erythrocytes in sepsis lead to the release of intracellular contents, such as cell-free hemoglobin, into circulation, worsening sepsis-induced organ damage in the lungs and kidneys[45–49]. The irons released from cell-free hemoglobin also contributed to bacterial growth and inflammation[50, 51]. In addition, erythrocytes are involved in immune regulation by controlling the function of T lymphocytes, macrophages and DCs through surface molecules, and they can also adsorb and kill bacteria in circulation before presenting them to APCs for phagocytosis[52]. Therefore, in sepsis patients, ADRB2 may be regulated by hsa-miR-34b-3p and subsequently affects SPTB function, leading to abnormal erythrocytes in vivo, releasing intracellular contents, and preventing erythrocyte immune function, ultimately worsening sepsis.