The actin-regulatory protein Hem-1 is essential for alveolar macrophage development

Abstract

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.

Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

“…Indeed, by examining the causal genes for immunodeficiency that were upregulated in myeloid phagocytes, we found TET2 and WAS upregulated in bone marrow, and ATP6AP1 and NCKAP1L upregulated in spleen. Intriguingly, all four disease genes are known to participate in signaling pathways associated with myeloid-phagocytes–mediated immunity (Banks et al, 2021; Brunetti et al, 2022; Stahnke et al, 2021; Suwankitwat et al, 2021; Yang et al, 2020). These findings suggest that disease genes that are upregulated in the receptor-bearing cell type might be involved in a downstream signaling pathway.…”

Single cell RNA sequencing reveals mechanisms underlying a senescence-like phenotype of Alveolar Macrophages during Aging

“…2B). Furthermore, Cbfb, but not any of the other transcription factors known to be important for AM development and/or proliferation [10][11][12][13][14] corelated with the pattern of G2/M phase score and the expression of proliferation marker, Mki67 (Fig 2B).…”

“…To this end, AMs depend on GM-CSF and autocrine TGF-b signaling for their maturation, proliferation and maintenance 3,8,9 . Transcription factors including PPAR-g 10 , BHLHE40 and BHLHE41 11 , Bach2 12 , Hem-1 13 as well as EGR2 14 have been reported to be indispensable for the generation and/or maintenance of the AM compartment. Furthermore, mitochondrial-dependent oxidative metabolisms are also vital for AM self-renewal and maintenance 15,16 .…”

HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions

“…Like mouse models of HEM1 deficiency, defects in neutrophil, dendritic cell, and macrophage migration and phagocytosis impair innate immune defenses, predisposing patients to bacterial infections [32][33][34][35]. Interestingly, myeloid-specific knockout of Hem1 in mice increased susceptibility to infection and morbidity upon influenza A and Streptococcus pneumoniae challenge [36]. Poor pathogen clearance, accumulation of debris, and excess cytokine production by alveolar macrophages may predispose patients to recurrent infections and long-term lung injury.…”