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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