Bone Marrow-Derived Mesenchymal Stromal Cells (MSCs) Modulate the Inflammatory Character of Alveolar Macrophages from Sarcoidosis Patients

Abstract

Sarcoidosis is a devastating inflammatory disease affecting many organs, especially the lungs and lymph nodes. Bone marrow-derived mesenchymal stromal cells (MSCs) can “reprogram” various types of macrophages towards an anti-inflammatory phenotype. We wanted to determine whether alveolar macrophages from sarcoidosis subjects behave similarly by mounting an anti-inflammatory response when co-cultured with MSCs. Fifteen sarcoidosis and eight control subjects underwent bronchoscopy and bronchoalveolar lavage (BAL). Unselected BAL cells (70–94% macrophages) were isolated and cultured with and without MSCs from healthy adults. Following stimulation of the cultured cells with lipopolysaccharide, the medium was removed to measure interleukin 10 and tumor necrosis factor alpha (IL-10 and TNF-α). In two additional sarcoidosis subjects, flow cytometry was used to study intracellular cytokines and surface markers associated with alveolar macrophages to confirm the results. Unselected BAL cells from sarcoidosis subjects co-cultured with MSCs showed a reduction in TNF-α (pro-inflammatory M1) and an increase in IL-10 (anti-inflammatory M2) in 9 of 11 samples studied. Control subject samples showed few, if any, differences in cytokine production. Unselected BAL cells from two additional patients analyzed by flow cytometry confirmed a switch towards an anti-inflammatory state (i.e., M1 to M2) after co-culture with MSCs. These results suggest that, similarly to other macrophages, alveolar macrophages also respond to MSC contacts by changing towards an anti-inflammatory phenotype. Based on our results, we hypothesize that mesenchymal stromal cells applied to the airways might alleviate lung inflammation and decrease steroid need in patients with sarcoidosis.

Pulmonary Sarcoidosis: Experimental Models and Perspectives of Molecular Diagnostics Using Quantum Dots

“…In cells obtained from patients with sarcoidosis, a 20-fold decrease in the concentration of TNF-α-which characterises the pro-inflammatory phenotype M1-and a 50-fold increase in the concentration of IL-10-a marker of the anti-inflammatory phenotype M2-were revealed in comparison with cultures without adding BM-MSCs. BAL from healthy donors did not demonstrate changes of cytokine synthesis during the addition of BM-MSCs [19].…”

Differential Effects of Cytokine Versus Hypoxic Preconditioning of Human Mesenchymal Stromal Cells in Pulmonary Sepsis Induced by Antimicrobial-Resistant Klebsiella pneumoniae

“…While these levels typically exceed 3.5 in the BAL and so cannot be approximated to this animal model, it should be taken into consideration should sarcoidosis be a comorbidity in sepsis patients receiving MSC therapy. Current studies in MSC therapy for sarcoidosis focus on the phenotype shift from M1 to M2 alveolar macrophage functions [ 49 ], and so, further investigations are needed especially considering the findings portrayed in this study. Another study on infant acute lung injury during viral infection showed that there is a correlation between a reduced CD4 + to CD8 + ratio and lung damage and so brings credence to the clinical trials involving MSCs as a therapeutic for COVID-19 infections [ 50 ].…”

Models Contribution to the Understanding of Sarcoidosis Pathogenesis: “Are There Good Models of Sarcoidosis?”

“…Similarly, Isohisa et al showed an increased immunostaining for CD163 in cutaneous sarcoidosis [ 72 ]. Recently, BAL cells from sarcoidosis subjects co-cultured with MSCs showed a reduction in TNF-α (pro-inflammatory M1) and an increase in IL-10 (anti -inflammatory M2) [ 73 ]. Obviously, it is quite difficult to establish a real consensus on macrophages polarization in sarcoidosis.…”