Alveolar macrophage metabolic programming via a C-type lectin receptor protects against lipo-toxicity and cell death.

Alveolar macrophages (AM) hold lung homeostasis intact. In addition to the defense against inhaled pathogens and deleterious inflammation, AM also maintain pulmonary surfactant homeostasis, a vital lung function that prevents pulmonary alveolar proteinosis. Signals transmitted between AM and pneumocytes of the pulmonary niche coordinate these specialized functions. However, the mechanisms that guide the metabolic homeostasis of AM remain largely elusive. We show that the NK cell-associated receptor, NKR-P1B, is expressed by AM and is essential for metabolic programming. Nkrp1b^−/− mice are vulnerable to pneumococcal infection due to an age-dependent collapse in the number of AM and the formation of lipid-laden AM. The AM of Nkrp1b^−/− mice show increased uptake but defective metabolism of surfactant lipids. We identify a physical relay between AM and alveolar type-II pneumocytes that is dependent on pneumocyte Clr-g expression. These findings implicate the NKR-P1B:Clr-g signaling axis in AM-pneumocyte communication as being important for maintaining metabolism in AM. Alveolar macrophages (AM) in the lungs maintain surfactant during homeostasis and respond to infectious pathogens. Here the authors show that in the absence of NKR-P1B, pneumococcal infection is more severe because KO AM have increased rates of lipid surfactant uptake and reduced anti-microbial function. [ABSTRACT FROM AUTHOR]