Sepsis, February 23 edition

Sepsis, a systemic inflammatory response to infection, remains a leading cause of mortality in intensive care units, with sepsis-induced immunosuppression being a critical pathophysiological process. In this study, we investigated the role of histone deacetylase 1 (HDAC1) in sepsis-induced CD8+ T cell exhaustion, a key driver of immunosuppression. Clinical analyses of patients with sepsis revealed that reduced peripheral blood lymphocyte levels, particularly CD8+ T cell depletion, strongly correlated with worsened outcomes. In a murine sepsis model, single-cell RNA-Seq revealed a significant decrease in the proportion of CD8+ T cells and an increase in the proportion of exhausted CD8+ T cells in mouse lungs. Adoptive transfer of CD8+ T cells effectively reduced sepsis mortality by preserving organ function. We further demonstrated that HDAC1 expression was significantly upregulated in CD8+ T cells from patients with sepsis. In vitro studies showed that HDAC1 inhibition preserved CD8+ T cell function by maintaining T cell activity and reducing the expression of inhibitory molecules such as PD-1. Pharmacological inhibition of HDAC1 reduced mortality and reversed CD8+ T cell exhaustion by restoring the balance between activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT). Additionally, we found that HDAC1 directly interacted with NFAT1, promoting its nuclear translocation and further enhancing the expression of inhibitory molecules. Our findings highlight HDAC1 as a potential therapeutic target for sepsis-induced immunosuppression. By elucidating the molecular mechanisms underlying HDAC1-mediated immunosuppression, we have provided potential strategies for developing immunomodulatory therapies for the treatment of sepsis.

INTRODUCTION: Sepsis-associated acute kidney injury (SA-AKI) is frequently complicated by immune paralysis and kidney infection. Despite the spleen's critical immunological role, the neural mechanisms regulating the splenic immune responses during SA-AKI remain unclear. METHODS: To examine this, we used splenic denervation, continuous intrasplenic infusion, single-cell sequencing and neutrophil-specific β2 adrenergic receptor Adrb2 knockout mice to define the role of the splenic norepinephrine-β2-adrenergic receptor (NE/β2-AR) axis in SA-AKI. RESULTS: Our findings indicate that pre-emptive splenic denervation in mice mitigates sepsis-induced kidney injury, whereas local intrasplenic norepinephrine infusion exacerbates kidney damage in a cecal ligation/puncture (CLP) mouse model. Targeted blockade of splenic β2-adrenergic receptor (β2-AR) signaling enhances survival and attenuates kidney damage in CLP mice. Local splenic depletion of neutrophil and neutrophil-specific conditional knockout of Adrb2 demonstrates that NE/β2-AR signaling influences splenic neutrophils, thereby driving the progression of acute sepsis. Mechanistic investigations reveal that splenic NE/β2-AR signaling enhances neutrophil prostaglandin E2 synthesis via the cAMP-response element binding protein pathway, thereby suppressing T helper 1 cell activation, increasing local bacterial infections, and aggravating SA-AKI. CONCLUSIONS: These findings clarify the role of splenic NE/β2-AR signaling in modulating neutrophil-mediated immunosuppression, thereby driving sepsis progression and aggravating kidney damage.

Sepsis-induced liver injury involves profound immune dysregulation. Natural compounds such as artesunate (ART), capsaicin (CAP), and oridonin (ORI) have demonstrated efficacy in mitigating systemic inflammation; however, their comparative cellular mechanisms in sepsis remain poorly characterized. Here, we integrated and reanalyzed the single-cell transcriptomic datasets of murine livers from 5 conditions: healthy control, sepsis, and sepsis treated with ART, CAP, or ORI. We uncover a spectrum of neutrophil subtypes with treatment-responsive phenotypes, including anti-inflammatory Ngp+ Neu1, immunosuppressive Cd274+ Neu2, and mature Stfa2l1+ Neu4, in which the excessive neutrophil expansion was suppressed by all 3 therapies through distinct regulon activities. Macrophages were activated and infiltration to partially rebalance immune homeostasis. Endothelial cells underwent profound reprogramming under sepsis, marked by NF-κB activation and oxidative stress, which are selectively modulated by treatment. Cell-cell communication analysis revealed a convergent dampening of inflammatory ligand-receptor networks, including the CCL signaling axis, and therapy-specific enhancement of regenerative cues, such as EGF signaling. Our findings reveal both shared and compound-specific immunoregulatory effects of ART, CAP, and ORI, offering mechanistic insights into hepatic immune rebalancing in sepsis. This single-cell atlas provides a conceptual framework for the rational design of multitarget therapies and highlights the key immune modules amenable to therapeutic intervention.