EML4 Deficiency as a Novel Cause of Alveolar Macrophage Dysfunction and Interstitial Lung Disease

Aiden Telfser – Garvan Institute of Medical Research; Robert Brink – Garvan Institute of Medical Research; Stuart Tangye – Garvan Institute of Medical Research; Tri Phan – Garvan Institute of Medical Research; Chetan Pandit – The Children's Hospital at Westmead; Paul Gray – Sydney Children's Hospital; Peter Hsu – The Children's Hospital at Westmead; Elissa Deenick – Garvan Institute of Medical Research

Abstract Text: Alveolar macrophages (AMs) play a critical role in maintaining lung homeostasis. Thus, identifying regulators of their function is important to understanding the pathogenesis of lung disease. Two siblings born to consanguineous parents presented with early onset progressive interstitial lung disease and a pulmonary alveolar proteinosis (PAP)-like phenotype, as well as failure to thrive and atopy. We identified homozygous deletions in the EML4 gene, encoding the Echinoderm microtubule-associated protein-like 4 (EML4), in both children. EML4 deficiency has not been reported previously, and there is limited literature regarding its function. Thus, we generated mice with a similar deletion in Eml4 to examine the role of EML4 in lung immunology and to understand the clinical features of the patients.

Analysis of EML4-deficient mouse lungs revealed a decrease in AMs, with scRNA-seq demonstrating the most differentially expressed genes in this population, compared to WT mice. AMs from EML4-deficient mice also had increased lipid content, consistent with the foamy macrophages in the patients’ lungs.

EML4-deficient mice did not demonstrate lung pathology under pathogen free conditions. However, exposure to influenza virus or a more diverse microbiota by co-housing with ‘dirty’ mice led to significant lung damage and immune infiltration EML4-deficient mice.

Importantly, bone marrow transplant from WT mice restored AM numbers in EML4-deficient mice, with scRNA-seq demonstrating a correction of the AM phenotype. This suggests a possible treatment option for affected patients.

Thus, we report the first cases of human complete EML4 deficiency and identify EML4 as a critical regulator of AM function and lung homeostasis.