A common immune-boosting sugar (β-glucan) protects liver immune cells in sepsis and helps clear bacteria in mice.

Objective
Determine whether β-glucan preserves liver Kupffer cells (KCs) during sepsis and improves antibacterial defense, and define underlying mechanisms, specifically inflammasome/pyroptosis inhibition and KC self-renewal programs. 

Methods

• Murine cecal ligation and puncture (CLP) sepsis model with KC quantification at 6 h and 24 h; KC loss correlated with severity (hypothermia). 
• β-glucan was given twice over 7 days before CLP (with an additional test of first dose 2 h post-CLP). 
• In vitro, THP-1 and BMDMs were co-stimulated with heme (10 μM) and heat-killed E. coli to model DAMP + pathogen signals.
• Outcomes included propidium iodide cell death, CyQUANT, LDH, NLRP3/ASC/GSDMD cleavage immunoblots, ASC speck imaging, and IL-1β ELISA.
• KC self-renewal was assayed by BrdU incorporation, Ki-67 and phospho-Histone H3 (P-H3) staining, and expression of c-Maf/MafB (qPCR). 
• Antibacterial function was assessed by GFP-E. coli capture in situ and bacteremia CFU after IV challenge with live E. coli. 

Results

• Sepsis drives KC loss that is associated with worse outcomes (lower body temperature). 
• Heme + bacteria synergistically trigger pyroptosis in macrophages with increased NLRP3, ASC, and cleaved GSDMD; cell death rose to ~40–45% and viability fell, versus modest effects of either stimulus alone. 
• β-glucan protects KCs in vivo: pre-treatment preserved Clec4F⁺ KCs at 6 h and 24 h; post-CLP dosing yielded modest but significant preservation. 
• β-glucan attenuates pyroptosis: reduced cell death, decreased NLRP3, cleaved GSDMD, ASC specks, and IL-1β release under heme + bacteria co-stimulation. 
• β-glucan promotes KC self-renewal: increased BrdU⁺F4/80⁺, Clec4F⁺Ki-67⁺, and Clec4F⁺P-H3⁺ cells; increased c-Myc in KCs; decreased c-Maf and MafB transcripts. Ex vivo KCs mirrored these findings. 

Enhanced antibacterial clearance: more F4/80⁺/GFP-E. coli co-localization in liver and lower blood CFU at 20 min and 24 h post-infection; β-glucan also increased macrophage uptake of GFP-E. coli in vitro.

Interpretation
β-glucan confers dual protection in sepsis: (1) anti-pyroptotic action (suppression of NLRP3-ASC-GSDMD axis) preventing KC death; and (2) pro-regenerative action (down-tuning c-Maf/MafB and boosting proliferative markers) that restores the KC pool. Together these effects improve hepatic bacterial capture and reduce bacteremia, supporting β-glucan as an immunomodulatory strategy to maintain liver innate immunity during sepsis. 

Mechanisms and pathways discussed

• Inflammasome/pyroptosis: heme + bacteria leads to increased NLRP3/ASC, GSDMD cleavage resulting in pyroptotic death; β-glucan blunts this cascade (fewer ASC specks, less cleaved GSDMD, less IL-1β). 
• Self-renewal program: β-glucan downregulates c-Maf/MafB (self-renewal repressors), upregulates c-Myc, and increases Ki-67/P-H3, indicating KC proliferation rather than replacement by monocyte-derived cells. 

Dosages and adverse reactions

• In vivo regimen: WT mice were treated with 0.5 mg β-glucan via I.P. via 2 injections over 7 days, one injection on day 0 and day 3; a separate cohort received β-glucan 2 h after CLP. 
• In vitro: heme 10 μM; E. coli MOI 10; 3–24 h exposures. 
• Adverse reactions not reported.

Quality of study 
Strengths: clinically relevant CLP model; orthogonal mechanistic endpoints (histology, BrdU/Ki-67/P-H3, ASC specks, IL-1β, inflammasome WB); demonstration of both prevention and post-insult protection; functional readouts for bacterial capture and CFU; inclusion of human (THP-1) and murine (BMDM) macrophages. 

Limitations: survival outcomes not reported here; translational unknowns (β-glucan class/formulation). Overall, robust mechanistic preclinical evidence with clear biologic plausibility, pending dosing and survival validation. 

Implications
In sepsis, preserving KC integrity is pivotal. β-glucan’s inflammasome-sparing and self-renewal-promoting effects suggest a potential immunoadjunct to reduce bacterial burden and protect hepatic immune homeostasis. More dose-defined preclinical survival studies and early-phase clinical exploration are needed for deeper understanding.