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Updated: Jul 10, 2026
Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
Alveolar macrophage suppression in sepsis is associated with high mobility group box 1 transmigration
Madhuri Pahuja1, Cindy Tran, Haichao Wang
1Department of Cell Biology, University of Medicine and Dentistry, NJ-School of Osteopathic Medicine, Stratford, NJ 08084, USA.
Abstract:
Macrophage dysfunction occurs late in sepsis and is implicated in increased mortality. Interferon gamma (IFN-gamma) stimulates transmigration of high mobility group box 1 (HMGB-1) from the nucleus into cytoplasm of macrophages and subsequent release. Because HMGB-1 release also occurs late, and because one of the actions of HMGB-1 in the nucleus is to enhance transcription factors, we investigated if HMGB-1 transmigration is involved in macrophage suppression in sepsis. Alveolar macrophages were isolated 12 and 24 h from sham controls, cecal ligation and puncture (CLP), and CLP rats given IFN-gamma antibody (1.2 mg/kg, i.v.). All injections were given immediately after surgery. At 12 h, 60% of cells from sham controls had HMGB-1 located primarily in the nucleus, whereas 35% of cells had diffuse staining in both cytoplasm and nucleus. In CLP rats, HMGB-1 was located predominantly in the cytoplasm of 37% of cells, and 48% had diffuse staining, whereas in IFN-gamma antibody (Ab)-treated rats, HMGB-1 was located predominantly in the nucleus of 56% of cells, whereas 32% had diffuse staining. At 24 h, most cells from CLP rats (82%) had HMGB-1 located in the cytoplasm, whereas in contrast, HMGB-1 was located in the nucleus of 80% and 82% of cells from sham control and IFN-gamma Ab-treated rats, respectively. Gene expression of TNF-alpha was not significantly changed 12 h after surgery, but at 24 h, alveolar macrophages from CLP rats had reduced gene expression of TNF-alpha. Interferon gamma Ab treatment prevented the reduction in TNF-alpha gene expression. TNF-alpha release was not altered at 12 h. At 24 h, LPS-stimulated release of TNF-alpha was decreased in macrophages from CLP rats compared with sham controls. Interferon gamma Ab treatment prevented the decrease in LPS-stimulated TNF-alpha release. The results suggest that alveolar macrophage suppression after CLP is associated with HMGB-1 transmigration out of the cell nucleus and provides evidence that intranuclear HMGB-1 may play an integral role in macrophage activation in sepsis.
Insights
Sepsis impairs macrophage function by causing High Mobility Group Box 1 (HMGB-1) to move from the nucleus to the cytoplasm. Blocking this movement with interferon gamma antibody restores macrophage activation and TNF-alpha production.
Area of Science:
- Immunology
- Cell Biology
- Sepsis Pathophysiology
Background:
- Macrophage dysfunction is a late complication of sepsis, contributing to mortality.
- High Mobility Group Box 1 (HMGB-1) release from macrophages is observed late in sepsis.
- Intranuclear HMGB-1 enhances transcription factors, suggesting a role in macrophage activation.
Purpose of the Study:
- To investigate the role of HMGB-1 transmigration in sepsis-induced macrophage suppression.
- To determine if interferon gamma (IFN-gamma) influences HMGB-1 localization in sepsis.
- To assess the impact of HMGB-1 nuclear retention on macrophage function during sepsis.
Main Methods:
- Alveolar macrophages were isolated from sham-operated and cecal ligation and puncture (CLP) rats at 12 and 24 hours post-surgery.
- Rats received either saline or IFN-gamma antibody immediately after CLP.
- HMGB-1 localization was assessed by immunofluorescence; TNF-alpha gene expression and LPS-stimulated release were measured.
Main Results:
- In CLP rats, HMGB-1 predominantly localized to the cytoplasm by 24 hours, unlike sham controls where it remained nuclear.
- IFN-gamma antibody treatment prevented HMGB-1 cytoplasmic translocation and maintained nuclear localization.
- CLP rats showed reduced TNF-alpha gene expression and LPS-stimulated release at 24 hours, which was restored by IFN-gamma antibody treatment.
Conclusions:
- Sepsis-induced alveolar macrophage suppression is associated with the translocation of HMGB-1 from the nucleus to the cytoplasm.
- Intranuclear HMGB-1 appears crucial for maintaining macrophage activation in sepsis.
- Interferon gamma plays a role in regulating HMGB-1 localization and subsequent macrophage function during sepsis.
