Sepsis, a life-threatening organ dysfunction resulting from a dysregulated host response to infection, initiates a complex immune response that varies over time, characterized by sustained excessive inflammation and immunosuppression. Sepsis-induced immunosuppression is now recognized as a major cause of septic death, and identifying effective strategies to counteract it poses a significant challenge. This immunosuppression results from the disruption of immune homeostasis, characterized by the abnormal death of immune effector cells, hyperproliferation of immune suppressor cells, release of anti-inflammatory cytokines, and expression of immune checkpoints. Preclinical studies targeting immunosuppression, particularly with immune checkpoint inhibitors, have shown promise in reversing immunocyte dysfunctions and establishing host resistance to pathogens. Here, our review highlights the mechanisms of sepsis-induced immunosuppression and current diagnostic biomarkers, as well as immune-enhancing strategies evaluated in septic patients and therapeutics under investigation.

Dry eye is one of the most common ocular surface diseases caused by tear film instability and ocular surface damage due to an abnormal quality or quantity of tears. Inflammatory factors can initiate relevant transduction signalling pathways and trigger the inflammatory cascade response, resulting in ocular surface inflammation. It has been shown that the active ingredients in Dendrobium, such as polysaccharides, alkaloids and phenols, have anti-inflammatory, anti-tumour and immunity-boosting effects, and Dendrobium officinale extract can improve glandular secretion function, increase salivary secretion and increase the expression level of water channel protein in salivary glands in patients with dry eye syndromes. We investigated the in vitro cytoprotective effect of Dendrobium extracts in sodium chloride induced hyperosmotic conditions in human cornea keratocytes (HKs). Results showed that Dendrobium officinale Kimura et Migo water extract (DOW) and Dendrobium loddigesii Rolfe water extract (DLW) could upregulate the expression of aquaporins (AQP)5 protein, thus exerting a repairing effect by promoting cell migration. Furthermore, oral administration of DOW and DLW enhanced tear production in rats and exerted a protective effect on ocular surface damage. DOW and DLW could upregulate the expression of AQP5 and mucin (muc)5ac proteins in the lacrimal gland and reduce the inflammatory response. DOW and DLW inhibited the activation of the corresponding mitogen-activated protein kinases (MAPK) and NF-KB pathway, thereby playing a role in improving dry eye symptoms. This study provides a new perspective on dry eye treatment, and DOW and DLW may be potential therapeutic agents for dry eye.

Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Interleukin 40 (IL-40), a novel cytokine with immune regulatory functions in human diseases, was elevated at admission in two independent cohorts of patients with sepsis. High levels of secreted IL-40 in septic patients were positively correlated with PCT, CRP, lactate (LDH), and Sequential Organ Failure Assessment (SOFA) scores, in which IL-40 levels were used to stratify the early death of critically ill patients with sepsis. Moreover, genetic knockout of IL-40 (IL-40−/−) improved outcomes in mice with experimental sepsis, as evidenced by attenuated cytokine storm, multiple-organ failure, and early mortality, compared with those of wild-type (WT) mice. Mechanistically, single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) have revealed that S100A8/9hi neutrophil influx into the peritoneal cavity along with neutrophil extracellular trap (NETs) formation accounts predominantly for the IL-40-mediated worsening of sepsis outcomes. Clinically, the IL-40 level was positively correlated with the NET-related MPO/dsDNA ratio in septic patients. Finally, with antibiotics (gentamycin), genetic knockout of IL-40 prevented polymicrobial sepsis fatalities more efficiently than without gentamycin treatment. In summary, these data reveal a novel prognostic strategy for sepsis and that IL-40 may serve as a novel therapeutic target for sepsis.

The persistent challenge of sepsis-related mortality underscores the necessity for deeper insights. Our multicenter, cross-age cohort study identified insulin-like growth factor binding protein 6 (IGFBP6) as a critical regulator in sepsis diagnosis, prognosis, and mortality risk evaluation. Mechanistically, IGFBP6 engages in IGF-independent binding to prohibitin2 (PHB2) on epithelial cells, driving PHB2 tyrosine phosphorylation during sepsis. This process disrupts STAT1 phosphorylation, nuclear translocation, and its recruitment to the CCL2 promoter, ultimately impairing CCL2 transcription and macrophage chemotaxis. Crucially, PHB2 silencing via siPHB2 and STAT1 activation using 2-NP restored CCL2 expression in vitro and in vivo, improving bacterial clearance and survival in septic mice. Concurrently, IGFBP6 compromised macrophage bactericidal activity by inhibiting Akt phosphorylation, reducing ROS/IL-1β production and phagocytic capacity — defects reversible by Akt agonist SC79. Collectively, IGFBP6 emerges as an endogenous driver of sepsis pathogenesis, positioning it as a dual diagnostic biomarker and therapeutic target. Intervention strategies targeting IGFBP6-mediated signaling may offer transformative approaches for sepsis management.