Abstract
The current paradigm for explaining lung granulomatous diseases induced by inhaled particles is mainly based on macrophages. This mechanism is now challenging because B lymphocytes also infiltrate injured tissue, and the deficiency in B lymphocytes is associated with limited lung granulomas in silica-treated mice. Here, we investigated how B lymphocytes respond to micro- and nanoparticles by combining in vivo and in vitro mouse models. We first demonstrated that innate-like B-1 lymphocytes (not conventional B-2 lymphocytes or plasma cells) specifically accumulated during granuloma formation in mice instilled with crystalline silica (DQ12, 2.5 mg/mouse) and carbon nanotubes (CNT Mitsui, 0.2 mg/mouse). In comparison to macrophages, peritoneal B-1 lymphocytes purified from naïve mice were resistant to the pyroptotic activity of reactive particles (up to 1 mg/mL) but clustered to establish in vitro cell/particle aggregates. Mouse B-1 lymphocytes (not B-2 lymphocytes) in coculture with macrophages and CNT (0.1 µg/mL) organized three-dimensional spheroid structures in Matrigel and stimulated the release of TIMP-1. Furthermore, purified B-1 lymphocytes are sensitive to nanosilica toxicity through radical generation in culture. Nanosilica-exposed B-1 lymphocytes released proinflammatory cytokines and alarmins. In conclusion, our data indicate that in addition to macrophages, B-1 lymphocytes participate in micrometric particle-induced granuloma formation and display inflammatory functions in response to nanoparticles.
Highlights
Excessive inhalation of toxic particles has been associated with the development of multiple respiratory manifestations, such as granuloma formation, fibrosis and cancer (Bierkandt et al 2018)
B‐1 lymphocytes accumulate during the development of particle‐induced pulmonary granuloma and fibrosis at late time points after silica treatment (± 20% from day 15 to day 60, Fig. 1b) but not at early points (1–7 days)
Animals were treated with tungsten carbide (WC), an inert particle that does not induce granuloma or fibrosis (Huaux et al 1999), and carbon nanotubes (CNT), which induce robust fibrotic granulomas (Khaliullin et al 2017)
Summary
Excessive inhalation of toxic particles has been associated with the development of multiple respiratory manifestations, such as granuloma formation, fibrosis and cancer (Bierkandt et al 2018). The accumulation of particles in the pulmonary alveoli causes tissue damage and activates resident macrophages During this acute response to particles, these phagocytes execute essential functions by clearing particles. Granuloma M2-polarized macrophages participate in the development of fibrosis by activating fibroblasts and induce exaggerated tissue repair (Lebrun et al 2017; Zhao et al 2020). The persistence of this process leads to excessive extracellular matrix protein deposition and irreversible granulomatous fibrous scarring, thereby decreasing lung capacity (Malaviya et al 2020). Preventing abnormal extracellular matrix remodeling after reactive particle instillation using metalloproteinase inhibitor-deficient mice markedly reduces fibrotic granulomatous lesion progression (Mohan et al 2020)
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