cGAS/STING signalling in macrophages aggravates obliterative bronchiolitis via an IFN‐α‐dependent mechanism after orthotopic tracheal transplantation in mice

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BACKGROUND: Our previous findings have underscored the role of innate immunity in obliterative bronchiolitis (OB). However, despite the central importance of the cyclic GMP‒AMP synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway in innate immune responses, its specific contribution to OB progression remains largely unexplored. METHODS: A murine orthotopic tracheal transplantation model was established to replicate OB pathogenesis. RNA sequencing and single-cell RNA sequencing data were analysed to investigate mechanisms underlying OB. Key molecules of the cGAS/STING pathway were assessed using immunofluorescence staining. Macrophage-specific Sting1 knockout mice were generated to investigate the role of the cGAS/STING pathway in OB. Haematoxylin and eosin staining and Masson's trichrome staining were utilised to evaluate allograft stenosis and fibrosis. Immune cell infiltration and cytokine expression were analysed using immunofluorescence staining and qRT-PCR. Flow cytometry was used to characterise splenic T-cell subsets and assess co-stimulatory molecule expression in macrophages. RESULTS: The cGAS/STING pathway was upregulated in macrophages infiltrating allografts. Macrophage-specific Sting1 knockout significantly attenuated alloreactive T-cell responses and alleviated OB. Furthermore, Sting1 deletion reduced the expression of inflammatory marker NOS2, antigen-presenting molecule MHC class II and co-stimulatory molecules (CD80 and CD86) in macrophages. Mechanistically, Sting1 knockout inhibited the production of interferon-α2 (IFN-α2), while the protective effect of macrophage-specific Sting knockout was reversed by IFN-α2 administration. Importantly, STING inhibition enhanced the allograft tolerance-promoting effects of cytotoxic T-lymphocyte-associated antigen 4-Ig (CTLA4-Ig), leading to the preservation of the airway epithelium. CONCLUSIONS: Our study demonstrated that cGAS/STING signalling pathway exacerbated allograft rejection in an IFN-α2-dependent manner. These findings provide insights into potential novel strategies for prolonging allograft survival. KEY POINTS: cGAS/STING signalling pathway was activated in macrophages infiltrating allografts. cGAS/STING signalling pathway in macrophages exacerbated allograft rejection, promoted antigen-presenting ability of macrophages and enhanced alloreactive T-cell responses in an IFN-α2-dependent manner. STING inhibition potentiated the therapeutic efficacy of CTLA4-Ig in OB.

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