Pyrroloquinoline quinone ameliorates inflammatory responses by modulating macrophage polarization in murine models of SLE and lupus-associated diffuse alveolar hemorrhage.

Abstract

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by complex immune dysregulation, including abnormalities in macrophage polarization. Pyrroloquinoline quinone (PQQ) has been reported to exert anti-inflammatory and immunoregulatory effects in various disease models, but its role in SLE remains unclear. OBJECTIVE: To evaluate the therapeutic effects of PQQ in SLE and SLE-associated diffuse alveolar hemorrhage (DAH) and to assess its impact on macrophage activation. METHODS: Pristane-induced DAH mice and lupus-prone MRL/lpr mice were used to assess in vivo efficacy. Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) analyses were performed to characterize immune remodeling and explore underlying mechanisms. RAW264.7 macrophages were used to examine the inhibitory effects of PQQ on M1 macrophage polarization. RESULTS: PQQ alleviated lung injury in SLE-DAH mice and reduced splenomegaly, autoantibodies, renal inflammation, and systemic cytokines in MRL/lpr mice. Flow cytometry and scRNA-seq consistently demonstrated reductions in inflammatory macrophage populations. Bulk RNA-seq further indicated that PQQ modulated inflammatory pathways associated with macrophage activation. Moreover, PQQ significantly reduced the expression of inflammatory mediators (IL-6, TNF-α, and IL-1β), inhibited M1 macrophage polarization, and decreased the production of oxidative stress-associated indicators (ROS and NO) in LPS/IFN-γ-stimulated RAW264.7 cells. Finally, PQQ regulated ERK/MAPK signaling, which contributed to the attenuation of inflammatory responses. CONCLUSION: PQQ attenuates SLE and its pulmonary complication DAH by regulating macrophage polarization and may serve as a potential immunomodulatory therapeutic candidate.