Revitalizing Alveolar Immunity: MSC role in Autoimmune Pulmonary Alveolar Proteinosis

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare interstitial lung disease characterized by granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. This leads to impaired surfactant clearance by alveolar macrophages (AMs) resulting in multiple immune disorders within the alveoli with AM dysfunction central to the pathophysiology of aPAP. Mesenchymal stem cells (MSCs) have been used to restore the immune environment through paracrine cytokines and growth factors in the treatment of several autoimmune diseases. We hypothesized that MSC treatment may restore alveolar macrophage dysfunction by improving the immune lung environment of patients with aPAP. Single-cell RNA sequencing (scRNA-seq) of bronchoalveolar lavage fluid (BALF) cells revealed three distinct subtypes of macrophages and their phenotypic transformation in patients with aPAP. AMs from patients with aPAP exhibited deficiencies in surfactant clearance and increased susceptibility to inflammation. Phagocytosis of primary pulmonary AMs of patients with aPAP were enhanced following MSC treatment. In vivo experiments demonstrated that MSCs were of benefit in gm-csf-/-mice by reducing the turbidity and protein levels of BALF and improving long-term survival. MSCs treatment reduce the enrichment of SPP1+ and AREG+ macrophage subsets in gm-csf-/-mice. Furthermore, SPP1+ macrophages showed a marked increase in the number and strength of outgoing and incoming signals, highlighting their central role in aPAP. In summary, MSC treatment improved the survival rate of gm-csf-/- mice by enhancing alveolar macrophage function. Three distinct macrophage subtypes with crucial roles in the development of aPAP have been identified that can be modified by MSCs.