Monocyte/macrophage NLRP3-IL-1β signaling drives myasthenia gravis pathogenesis in rats and patients

Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by pathogenic autoantibodies targeting the neuromuscular junction. While the role of adaptive immunity is well-established, the involvement of innate immune cells, particularly monocytes and macrophages, in MG pathogenesis remains unclear. This knowledge gap limits comprehensive therapeutic strategies. This study investigated whether the NLRP3 inflammasome-caspase-1-IL-1β pathway, a key component of innate immune activation, contributes to disease development in MG and its experimental model, potentially revealing novel therapeutic targets beyond current immunosuppressants.

Experimental autoimmune myasthenia gravis (EAMG) was induced in Lewis rats by immunization with AChR97-116 peptide. Splenic and lymph node CD11b/c+ macrophages were analyzed by flow cytometry at early (d14), middle (d30), and late (d46) disease stages. Bulk RNA sequencing was performed on sorted splenic CD11b/c+ macrophages from EAMG and control rats at d14. Peripheral blood mononuclear cells (PBMCs) were collected from 36 myasthenia gravis patients during clinical exacerbation and 35 healthy controls. Monocyte subsets and intracellular caspase-1/IL-1β expression were assessed by flow cytometry. Correlations with clinical severity (QMG score) and lymphocyte counts were analyzed.

In EAMG rats, the proportion of CD11b/c+ macrophages increased significantly in the spleen and lymph nodes during early and middle disease stages. These macrophages showed elevated expression of Nlrp3, Casp1, and Il1b genes, with enrichment of the NOD-like receptor signaling pathway. > The frequencies of CD11b/c+caspase-1+ and CD11b/c+IL-1β+ macrophages were significantly higher in early and middle stages compared to controls and late stage. In myasthenia gravis patients, the proportion of CD14+ monocytes increased during clinical exacerbation, with expansion of both classical (CD14++CD16-) and intermediate (CD14++CD16+) subsets. Classical monocytes exhibited elevated IL-1β expression, while intermediate monocytes showed increased caspase-1 expression, strongly linking innate immune activation via the NLRP3-IL-1β axis to MG pathogenesis.