Work

Exploring the Role of Neutrophils in Pathogenesis of Lymphangioleiomyomatosis

Year: 2026

Type: article

Abstract: BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare, slowly progressive neoplasm, predominantly affecting women, characterized by the presence of diffuse cystic lung disease. Its pathogenesis is driven by mutations in tuberous sclerosis complex (TSC) genes leading to mechanistic target of rapamycin (mTOR) pathway activation, with mTOR inhibitors licensed to slow disease progression. Emerging evidence implicates neutrophils in LAM pathogenesis through oestrogen signalling pathways. SUMMARY: Preclinical studies using TSC2 null mouse models demonstrate that oestrogen signalling promotes the expansion of neutrophils from bone marrow and recruitment to tumour sites. Immature myeloid-derived suppressor cells (MDSCs) create an immunosuppressive microenvironment that facilitates LAM tumour growth and metastasis. Neutrophil elastase (NE) is a key mediator, promoting tumour cell growth, migration, and invasion. Tumour burden is reduced in preclinical models on inhibition of NE or depletion of MDSCs. Clinical data validate these mechanisms, with elevation of neutrophil count and neutrophil-lymphocyte ratios (NLRs) correlating with accelerated lung function decline and increased incidence of pneumothorax. Both markers decrease following mTOR inhibitor therapy, suggesting pathway connections. KEY MESSAGES: The role of neutrophils in LAM pathogenesis appears to be mediated through oestrogen signalling pathways. Neutrophil counts and NLR are potential prognostic biomarkers for clinical practice. Potential neutrophil-directed therapies included NE inhibition and agents targeting oestrogen signalling. Further clinical investigation is warranted to translate these mechanistic insights into clinical practice.

Source: Journal of Innate Immunity

DOI: 10.1159/000552550

Authors: Donal O'Malley, Katie Ann Doran, Cormac McCarthy

Institution: University College Dublin

Language: English

Topic: Tuberous Sclerosis Complex Research

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,590