In a proportion of patients with hypersensitivity pneumonitis, biological and environmental factors sustaining inflammation are ill-defined, resulting in no effective treatment option. Bioaerosols found in occupational settings are complex and often include Toll-like receptor ligands, such as endotoxins. How Toll-like receptor ligands contribute to the persistence of hypersensitivity pneumonitis, however, remains poorly understood. In a previous study, we found that a sphingosine-1-phosphate receptor 1 agonist prevents the reactivation of antigen-driven B cell responses in the lung.
We assessed the impact of endotoxins on B cell activation in pre-existing hypersensitivity pneumonitis and the role of sphingosine-1-phosphate receptor 1 in this phenomenon.
The impact of endotoxins on pre-established hypersensitivity pneumonitis was studied . Sphingosine-1-phosphate receptor 1 levels were tracked on B cells in the course of the disease using S1P-eGFP knock-in mice; and the role of sphingosine-1-phosphate receptor 1 on B cell functions was assessed using pharmacological tools.
Sphingosine-1-phosphate receptor 1 is found on B cells in experimental hypersensitivity pneumonitis. Endotoxin exposure enhances neutrophil accumulation in the bronchoalveolar lavage of mice with experimental HP. This was associated with enhanced CD69 cell surface expression on lymphocytes in the bronchoalveolar lavage. In isolated B cells, endotoxins increase cell surface levels of co-stimulatory molecules and CD69, which is prevented by a sphingosine-1-phosphate receptor 1 agonist. Sphingosine-1-phosphate receptor 1 modulators also reduced TNF production by B cells and their capacity to trigger T cell cooperation .
A sphingosine-1-phosphate receptor 1 ligand directly inhibits endotoxin-induced B cell activation.

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