Nerandomilast attenuates idiopathic inflammatory myopathy-associated interstitial lung disease via inhibiting proliferation and differentiation of B cells.

BACKGROUND: Idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) is a severe autoimmune condition with limited treatment options. Phosphodiesterase 4B (PDE4B) is a key enzyme in the metabolism of cyclic adenosine monophosphate (cAMP) in lung tissue, and targeting PDE4B has been proposed as a promising therapeutic strategy. This study aimed to evaluate the therapeutic potential of Nerandomilast (a PDE4B inhibitor) in an experimental IIM-ILD model and to investigate its underlying mechanisms. METHODS: An IIM-ILD mouse model was established by immunization with skeletal muscle homogenate. Mice were treated with Nerandomilast (5 or 12.5 mg/kg, twice daily) or Nintedanib (60 mg/kg, once daily) as a positive control. Disease severity was assessed using myositis scores and spleen index. Pulmonary fibrosis and inflammation were evaluated via micro-CT, histopathology, and bronchoalveolar lavage fluid (BALF) analysis. B cell infiltration, activation, and differentiation were examined by flow cytometry, immunofluorescence, and Western blotting. Key signaling pathways were analyzed in lung tissue. RESULTS: Nerandomilast ameliorated muscle inflammation, pulmonary fibrosis, and pulmonary inflammation. Mechanistically, Nerandomilast targeted lung-infiltrating B cells: it inhibited their accumulation and proliferation, downregulated the activation marker BAFF, and suppressed their differentiation into plasma cells by reducing the expression of key transcription factors and the plasma cell marker. Serological testing indicated a significant decrease in anti-Jo-1 autoantibody positivity. At the molecular level, Nerandomilast elevated lung tissue cAMP levels, inhibited the phosphorylation of pro-survival/activation pathways (PI3K/AKT, NF-κB, STAT3) in B cells, and enhanced CREB phosphorylation. CONCLUSION: The PDE4B inhibitor Nerandomilast demonstrates potent therapeutic effects in a preclinical IIM-ILD model, alleviating both myositis and pulmonary pathology. Its efficacy is mechanistically linked to the direct modulation of B cells, achieved by elevating intracellular cAMP and subsequently reprogramming key signaling networks to inhibit B cell activation, proliferation, and pathogenic differentiation into antibody-producing plasma cells. These findings highlight Nerandomilast as a promising candidate for the treatment of IIM-ILD.