Absence of sympathetic innervation hampers the generation of tertiary lymphoid structures upon acute lung inflammation

Abstract

Abstract Background Tertiary lymphoid structures (TLS) are lymphoid organs present in inflammatory non-lymphoid tissues. Studies have linked TLS to favorable outcomes for patients suffering from cancers and infectious diseases, but the mechanisms underlying their formation are poorly elucidated. In particular, the innervation of secondary lymphoid organs raises the question of the involvement of sympathetic nerve fibers in TLS organogenesis. Methods We established a model of lipopolysaccharide-induced pulmonary inflammation based on 5 daily intranasal instillations in which lymphoid aggregates form and evolve toward mature TLS. Sympathetic nerve fibers were systemically depleted using 6-OHDA injections. TLS were analyzed and quantified using immunohistochemistry and immunofluorescence on lung tissue sections. Lung immune populations were assessed by flow cytometry, and the systemic primary immune response of denervated mice was analyzed by ELISA on plasma samples. Results Intranasal instillation of LPS in immunocompetent mice induced the transient formation of mature TLS in inflamed lungs. TLS disappeared when acute inflammation resolved. 6-OHDA treatment of LPS-treated animals provoked sympathetic fiber depletion that was associated with a decrease in pulmonary TLS density and with a reduction in lung alveolar space, although the depletion did not fully inhibit TLS formation. We showed a drop in the proportions of naive B cells in the lungs of denervated LPS-treated mice that also exhibited a decrease in their systemic primary antibody response. Conclusions These data support the existence of neuroimmune crosstalk involved in TLS neogenesis and function and in the control of the naive B-cell pool. Sympathetic nerve fibers could participate not only in TLS formation but also in the in situ mounting of strong primary antibody responses.