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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5 April 2021
Brief Definitive Report|
February 17 2021
The actin-regulatory protein Hem-1 is essential for alveolar macrophage development
Nutthakarn Suwankitwat
,
Nutthakarn Suwankitwat
Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft
1
Department of Comparative Medicine, University of Washington, Seattle, WA
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Stephen Libby
,
Stephen Libby
Methodology, Supervision
2
Department of Microbiology, University of Washington, Seattle, WA
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H. Denny Liggitt
,
H. Denny Liggitt
Investigation, Methodology, Supervision, Writing - review & editing
1
Department of Comparative Medicine, University of Washington, Seattle, WA
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Alan Avalos
,
Alan Avalos
Conceptualization, Investigation
1
Department of Comparative Medicine, University of Washington, Seattle, WA
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Alanna Ruddell
,
Alanna Ruddell
1
Department of Comparative Medicine, University of Washington, Seattle, WA
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Jason W. Rosch
,
Jason W. Rosch
Methodology, Writing - review & editing
3
Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN
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Heon Park
,
Conceptualization, Investigation, Methodology, Project administration, Resources, Validation, Writing - original draft, Writing - review & editing
1
Department of Comparative Medicine, University of Washington, Seattle, WA
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Brian M. Iritani
Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Comparative Medicine, University of Washington, Seattle, WA
Correspondence to Brian M. Iritani: biritani@uw.edu
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Nutthakarn Suwankitwat
Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft
1
Department of Comparative Medicine, University of Washington, Seattle, WA
Stephen Libby
Methodology, Supervision
2
Department of Microbiology, University of Washington, Seattle, WA
H. Denny Liggitt
Investigation, Methodology, Supervision, Writing - review & editing
1
Department of Comparative Medicine, University of Washington, Seattle, WA
Alan Avalos
Conceptualization, Investigation
1
Department of Comparative Medicine, University of Washington, Seattle, WA
Alanna Ruddell
1
Department of Comparative Medicine, University of Washington, Seattle, WA
Jason W. Rosch
Methodology, Writing - review & editing
3
Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN
Heon Park
Conceptualization, Investigation, Methodology, Project administration, Resources, Validation, Writing - original draft, Writing - review & editing
1
Department of Comparative Medicine, University of Washington, Seattle, WA
Brian M. Iritani
Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Comparative Medicine, University of Washington, Seattle, WA
Correspondence to Brian M. Iritani: biritani@uw.edu
Disclosures: The authors declare no competing financial interests.
*
H. Park and B.M. Iritani are co–senior authors.
Dr. Ruddell died on August 11, 2020.
Received:
March 11 2020
Revision Received:
September 16 2020
Accepted:
January 13 2021
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
National Institutes of Health
(R01AI092092)
© 2021 Suwankitwat et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (4): e20200472.
Article history
Received:
March 11 2020
Revision Received:
September 16 2020
Accepted:
January 13 2021
Citation
Nutthakarn Suwankitwat, Stephen Libby, H. Denny Liggitt, Alan Avalos, Alanna Ruddell, Jason W. Rosch, Heon Park, Brian M. Iritani; The actin-regulatory protein Hem-1 is essential for alveolar macrophage development. J Exp Med 5 April 2021; 218 (4): e20200472. doi: https://doi.org/10.1084/jem.20200472
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