Interleukin-6-Associated Pyroptosis, Apoptosis, and Necroptosis via JAKs/STAT3-RIPK1 Axis: A Potential Mechanism for...

Sepsis triggers both excessive inflammation and immunosuppression, the latter partly characterized by CD4 + T-cell depletion. The mechanisms underlying this depletion, especially its interplay with cytokine storms driven by inflammatory factors such as interleukin (IL)-6, remain unclear. This study aimed to elucidate the molecular mechanisms contributing to CD4 + T-cell depletion in sepsis, focusing specifically on the IL-6/Janus kinases (JAKs)/signal transducer and activator of transcription 3 (STAT3) signaling axis and programmed cell death.

Prospective cohort study.

Adult ICUs at a university hospital.

Adult sepsis and septic shock patients without any documented immune comorbidity.

None.

A prospective analysis enrolled 151 patients (93 sepsis, 58 septic shock) and 20 controls. Flow cytometry and enzyme-linked immunosorbent assay were used to assess immune cell populations and cytokine profiles, with multivariate analyses exploring their interrelationships. An additional 30 sepsis patients and ten controls were recruited to investigate mechanisms. Peripheral blood mononuclear cells (PBMCs) underwent RNA sequencing (RNA-seq). Isolated CD4 + T cells were stimulated with IL-6 in vitro, followed by treatment with specific inhibitors targeting pyroptosis, apoptosis, necroptosis, the JAKs/STAT3 pathway, or receptor-interacting protein kinase 1 (RIPK1). Western blotting, flow cytometry, immunofluorescence, Cell Counting Kit-8 assays, and interferon-gamma staining evaluated cell death pathways, PANoptosome (a complex mediating apoptosis, pyroptosis and necroptosis)-assembly, and function. Significant CD4 + T-cell loss occurred in both sepsis and septic shock groups, strongly correlating with elevated IL-6 levels. Sepsis PBMC RNA-seq revealed activated IL-6/JAKs/STAT3 signaling and upregulated apoptosis/pyroptosis/necroptosis genes. In vitro, IL-6 induced pyroptosis, apoptosis, and necroptosis (PANoptosis) in CD4 + T cells via IL-6/JAKs/STAT3-dependent RIPK1-PANoptosome assembly. Inhibiting JAKs/STAT3 or RIPK1 significantly reduced PANoptosis, partially restored CD4 + T-cell viability and functional capacity.

PANoptosis has been observed to be a form of CD4 + T-cell death in sepsis patients. Evidence suggests that IL-6 may be associated with the exhaustion process, mechanistically involving the activation of the JAKs/STAT3 pathway. It is also hypothesized that this process might be linked to RIPK1-PANoptosome-mediated PANoptosis.