Histone acetylation-regulated FBXO11-dependent degradation of BLIMP-1 promotes lung injury

Pediatric pneumonia, characterized by symptoms of fever and cough, presents certain challenges to clinical treatment due to a growing pathogen resistance and the difficulty of controlling inflammation in the immature pediatric immune system. Research on pediatric pneumonia has focused on the critical role of macrophage pyroptosis in pulmonary inflammation, with the aim of identifying novel therapeutic targets related to the modulation of inflammasome signaling pathways. The purpose of this study was to identify key genes associated with pediatric pneumonia and drugs that target these genes for the treatment of lung injury caused by the disease. Single-cell analysis revealed elevated F-box only protein 11 (FBXO11) expression in macrophages in patients with pediatric pneumonia.

Firstly, the target genes in patients with pediatric pneumonia were analyzed via polymerase chain reaction (PCR) and single-cell data analysis. C57BL/6 mice were intranasally challenged with colony-forming units (CFU) of Streptococcus pneumoniae. Murine bone marrow-derived macrophages (BMDMs) or RAW264.7 cells were treated with pectolinarigenin and liposaccharide (LPS), and then pulsed with adenosine triphosphate (ATP).

FBXO11 expression was upregulated in a pediatric pneumonia mice model, and small interfering RNA targeting F-box only protein 11 (si-FBXO11) alleviated lung injury in a mouse model of pediatric pneumonia. FBXO11 promoted macrophage pyroptosis in an in vitro pediatric pneumonia model. NOD-like receptor protein 3 (NLRP3) inhibitor treatment counteracted the propyroptotic effects of FBXO11 and B lymphocyte-induced maturation protein 1 (BLIMP-1) on macrophage pyroptosis in macrophages. FBXO11 suppressed BLIMP-1 expression and promoted its degradation in lung tissue from the pediatric pneumonia model. FBXO11 interlinked with BLIMP-1 and reduced BLIMP-1 expression and its ubiquitination. FBXO11 suppressed NLRP12 activity through the pyrin domain-containing 12 (NLRP12) promoter of the NOD-like receptor family at a BLIMP-1 binding site. Histone acetylation-regulated METTL3 enhanced FBXO11 messenger RNA (mRNA) stability through N(6)-methyladenosine (m⁶A) modification, thereby modulating pyroptosis. Pectolinarigenin bound to FBXO11 protein in macrophages and reduced macrophage pyroptosis in pediatric pneumonia.

FBXO11 promotes macrophage pyroptosis by degrading BLIMP-1 and suppressing the NLRP12 and NLRP3 signaling pathway, thereby exacerbating lung injury in pediatric pneumonia. Targeting this pathway may exert a therapeutic effect. Notably, pectolinarigenin represents a promising candidate for mitigating macrophage pyroptosis in pediatric pneumonia and possibly other pediatric inflammatory diseases.