In their work published in Nature Communications, Dr. Michal Scur and Dr. Andrew Makrigiannis demonstrate the importance of NKR-P1B and tissue-specific signaling in the immune reactivity of alveolar macrophages (AM) against pathogens, and in maintaining lung homeostatic mechanisms to prevent lipo-toxicity and cell death. 

 

Alveolar macrophages (AM) are lung-resident sentinel cells that regulate inflammatory responses in the alveolar epithelium and are vital for maintaining surfactant homeostasis. AMs metabolize pulmonary surfactant released by type II-pneumocytes and prevent pulmonary alveolar proteinosis (PAP), which can result in protein and mucous accumulations in the alveoli and eventual gas exchange failure. While AMs are integral for maintaining lung homeostasis, the mechanisms behind their inflammatory and metabolic functions are less well-understood. 

 

In this study, Scur et al. used Nkrp1b−/− mice to investigate the homeostatic mechanisms of AMs, given the importance of NKR-P1B, which is a conserved lectin-like inhibitory NK cell receptor, to the function and survival of AMs. The authors of this study saw increased morbidity and mortality in NKR-P1B-deficient mice in response to pneumococcal infections. This was attributed to a gradual loss of tissue-resident AMs, which were temporarily replaced with infiltrating monocytes that differentiated into AMs in a CCR2-dependent pathway. While these monocyte-derived AMs repopulated the alveolar niche, they still experienced homeostatic abnormalities. 

 

Moreover, resident AMs in Nkrp1b−/− mice were found to accumulate pulmonary surfactant-derived lipids, leading to an altered metabolic profile demonstrated by increased lipid uptake, storage, and processing. These AMs had a foam-like appearance, characteristic of metabolically-impaired AMs. AMs in NKR-P1B-deficient mice also demonstrated cell-cycle dysregulations and an inability to self-renew in vivo, which could be resolved by removing these AMs from a lipid-rich alveolar environment. Further analyses revealed the importance of NKR-P1B in preventing lipid accumulations in resident AMs. 

 

This study also suggests that in the context of infection, NKR-P1B may bind the C-type lectin protein (Clr)-g ligand, which is expressed on type-II pneumocytes, instead of its prototypical Clr-b ligand. Clr proteins are surfactant proteins and this finding alludes to the potential of an NKR-P1B-dependent link between innate immune regulation and surfactant homeostasis. 

 

Altogether, this work highlights the role of NKR-P1B in regulating the immunosurveillance and surfactant clearance functions of AMs in the alveolar epithelium.