Activation of GPR35 by kynurenic acid inhibits IL-1β secretion in macrophages during CR-hvKP-induced pneumonia

Carbapenemase-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is a common pathogen that can cause severe pneumonia. The innate immune response, especially the response of macrophages, plays a crucial role in the host's defense against bacterial infections. Glycolysis is implicated in the modulation of immune functions in macrophages. Here, we provide evidence supporting the role of GPR35 in decreasing glycolysis and reducing the secretion of IL-1β in macrophages by inhibiting the transcription of HK2 during K. pneumoniae-induced pneumonia. Mice with GPR35 knock-out exhibit higher mortality and increased lung bacterial burdens. Mechanistically, GPR35 activation by kynurenic acid inhibits caspase-1 cleavage and reduces IL-1β secretion in macrophages by specifically suppressing activation of the NLRP3 inflammasome. These findings underscore the role of GPR35 in regulating inflammation during K. pneumoniae-induced pneumonia and suggest that GPR35 is a potential therapeutic target for clinical treatment.