Myxomavirus serpin alters macrophage function and prevents diffuse alveolar hemorrhage in pristane-induced lupus
Haoyang Zhuang1, Shuhong Han1, Li Lu2
1Division of Rheumatology & Clinical Immunology, University of Florida, Gainesville, FL 32610, United States of America.
Abstract:
C57BL/6 mice with pristane-induced lupus develop macrophage-dependent diffuse alveolar hemorrhage (DAH), which is blocked by treatment with liver X receptor (LXR) agonists and is exacerbated by low IL-10 levels. Serp-1, a myxomavirus-encoded serpin that impairs macrophage activation and plasminogen activation, blocks DAH caused by MHV68 infection. We investigated whether Serp-1 also could block DAH in pristane-induced lupus. Pristane-induced DAH was prevented by treatment with recombinant Serp-1 and macrophages from Serp1-treated mice exhibited an anti-inflammatory M2-like phenotype. Therapy activated LXR, promoting M2 polarization and expression of Kruppel-like factor-4 (KLH4), which upregulates IL-10. In contrast, deficiency of tissue plasminogen activator or plasminogen activator inhibitor had little effect on DAH. We conclude that Serp-1 blocks pristane-induced lung hemorrhage by enhancing LXR-regulated M2 macrophage polarization and KLH4-regulated IL-10 production. In view of the similarities between DAH in pristane-treated mice and SLE patients, Serp-1 may represent a potential new therapy for this severe complication of SLE.
Insights
Serp-1, a viral protein, prevents lung hemorrhage in lupus-prone mice by promoting anti-inflammatory macrophages and IL-10 production. This suggests Serp-1 as a potential therapy for lupus-related lung complications.
Area of Science:
- Immunology
- Pulmonary Medicine
- Virology
Background:
- Pristane-induced lupus in C57BL/6 mice causes macrophage-dependent diffuse alveolar hemorrhage (DAH).
- Liver X receptor (LXR) agonists block DAH, while low IL-10 levels exacerbate it.
- Serp-1, a myxomavirus serpin, inhibits macrophage and plasminogen activation, previously shown to block DAH in MHV68 infection.
Purpose of the Study:
- To investigate the potential of Serp-1 to block DAH in a pristane-induced lupus model.
- To elucidate the mechanisms by which Serp-1 might exert its protective effects in DAH.
Main Methods:
- Treatment of C57BL/6 mice with pristane to induce lupus and DAH.
- Administration of recombinant Serp-1 to assess its therapeutic effect on DAH.
- Analysis of macrophage phenotype (M2 polarization) and expression of key regulatory factors (LXR, KLH4, IL-10).
- Evaluation of the role of plasminogen system components (tPA, PAI) in DAH.
Main Results:
- Recombinant Serp-1 treatment prevented pristane-induced DAH.
- Macrophages from Serp-1-treated mice displayed an anti-inflammatory M2-like phenotype.
- Serp-1 therapy activated LXR, leading to M2 polarization and increased Kruppel-like factor-4 (KLH4) expression, which subsequently upregulated IL-10.
- Deficiency in tissue plasminogen activator or plasminogen activator inhibitor had minimal impact on DAH development.
Conclusions:
- Serp-1 effectively blocks pristane-induced lung hemorrhage by enhancing LXR-regulated M2 macrophage polarization and KLH4-regulated IL-10 production.
- Given the similarities between murine DAH and SLE-associated lung complications, Serp-1 warrants consideration as a potential therapeutic agent for systemic lupus erythematosus (SLE).
