Open AccessThe actin-regulatory protein Hem-1 is essential for alveolar macrophage development
Author(s) -
Nutthakarn Suwankitwat,
Stephen J. Libby,
Denny Liggitt,
Alan Avalos,
Alanna Ruddell,
Jason W. Rosch,
Heon Park,
Brian M. Iritani
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20200472
Subject(s) - biology , immunology , myeloid , proinflammatory cytokine , pulmonary alveolar proteinosis , monocyte , lung , medicine , inflammation
Hematopoietic protein-1 (Hem-1) is a hematopoietic cell–specific actin-regulatory protein. Loss-of-function (LOF) variants in the NCKAP1L gene encoding Hem-1 have recently been found to result in primary immunodeficiency disease (PID) in humans, characterized by recurring respiratory infections, asthma, and high mortality. However, the mechanisms of how Hem-1 variants result in PID are not known. In this study, we generated constitutive and myeloid cell–specific Nckap1l-KO mice to dissect the importance of Hem-1 in lung immunity. We found that Hem-1–deficient mice accumulated excessive surfactant and cell debris in airways (pulmonary alveolar proteinosis) due to impaired development of alveolar macrophages (AMs) and reduced expression of the AM differentiation factor Pparg. Residual Hem-1–deficient AMs shifted to a proinflammatory phenotype, and Hem-1–deficient neutrophils and monocytes failed to migrate normally. Myeloid cell–specific Hem-1–deficient mice exhibited increased morbidity following influenza A virus or Streptococcus pneumoniae challenge. These results provide potential mechanisms for how LOF variants in Hem-1 result in recurring respiratory diseases.