Neutrophil hyperresponsiveness contributes to lung pathology in STAT3V463Δ mice

Area of Science:

• Immunology
• Genetics
• Pulmonology

Background:

• Autosomal dominant hyper-IgE syndrome (AD-HIES), or Job's syndrome, is a primary immunodeficiency linked to STAT3 mutations.
• AD-HIES patients suffer recurrent lung infections and chronic inflammation, elevating mortality risk.

Purpose of the Study:

• To investigate the role of neutrophil-intrinsic dysfunction in AD-HIES-associated lung pathology.
• To analyze the impact of the STAT3V463Δ mutation on neutrophil function and pulmonary inflammation.

Main Methods:

• Utilized a murine model expressing the STAT3V463Δ mutation.
• Administered intratracheal Pseudomonas aeruginosa infection and lipopolysaccharide (LPS) challenges.
• Assessed lung pathology, leukocyte infiltration, cytokine/chemokine levels, bacterial burden, neutrophil degranulation, and NETosis.

Main Results:

• STAT3V463Δ mice showed increased alveolar damage, vascular congestion, and leukocyte infiltration post-infection.
• Elevated pro-inflammatory cytokines, chemokines, and bacterial burden were observed in STAT3V463Δ mice.
• STAT3V463Δ neutrophils exhibited enhanced degranulation and NETosis, both in vivo and in vitro, independent of microbial load.

Conclusions:

• STAT3V463Δ mutation induces neutrophil hyperresponsiveness, contributing to lung pathology in AD-HIES.
• Neutrophil dysfunction plays a significant role in the pulmonary complications of AD-HIES.
• Targeting neutrophil hyperactivation may offer therapeutic strategies for AD-HIES.