The actin-regulatory protein Hem-1 is essential for alveolar macrophage development
Open accessAbstract
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.
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Myeloid-specific knockout of Hem1 in mice increased susceptibility to infection and morbidity upon influenza A and Streptococcus pneumoniae challenge.
“Interestingly, myeloid-specific knockout of Hem1 in mice increased susceptibility to infection and morbidity upon influenza A and Streptococcus pneumoniae challenge [36].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [36]
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The development and function of lung-resident macrophages and dendritic cells
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HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions
Cook, S., Lenardo, M. J., & Freeman, A. F. (2022) · Journal of Clinical Immunology · doi:10.1007/s10875-022-01327-0 · Cited by 24 · see citing works
- Authors
- Suwankitwat, N., Libby, S., Liggitt, H. D., Avalos, A., Ruddell, A., Rosch, J. W., Park, H., & Iritani, B. M.
- Affiliations
- University of Washington (US)
- Department of Comparative Medicine, University of Washington, Seattle, WA 1
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Iritani, Brian M.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2021-02-17
- Volume
- 218
- Issue
- 4
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC7894047
- OpenAlex
- W3133147568
- Cited by
- 18
- References
- 2
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 1
- FWCI
- 1.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01AI092092)
- Royal Thai Government
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- actin regulatory proteins, primary immunodeficiency, pulmonary alveolar proteinosis, surfactant accumulation, PPARγ, neutrophil migration, monocyte migration, influenza A virus, Streptococcus pneumoniae, lung immunity
- MeSH terms
- Actins, Animals, Cell Differentiation, Cell Movement, Cells, Cultured, Disease Models, Animal, Female, Lung, Male, Mice, Inbred C57BL, Monocytes, Neutrophils, Phagocytosis, Pulmonary Alveolar Proteinosis, Signal Transduction, Macrophages, Alveolar, Mice, Knockout, PPAR gamma, Adaptor Proteins, Signal Transducing, Mice
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