Background: Itaconate, generated by aconitate decarboxylase 1 which is encoded by immune-responsive gene 1 (Irg1), has been recognized as a novel therapeutic molecule for the treatment of inflammatory diseases. However, these anti-inflammatory effects are largely obtained in bone marrow-derived macrophages (BMDMs). It is unknown the role of itaconate in the activation of tissue-resident alveolar macrophages (tr-AMs) which exhibit distinct metabolic reprogramming upon activation.

Objective: To investigate if itaconate differentially affects the activation of BMDMs and tr-AMs by lipopolysaccharide and explore its potential mechanisms.

Result: We confirmed that itaconate suppresses the production of proinflammatory cytokines including IL-6 and IL-12 in BMDMs. However, these cytokines were significantly increased by the pretreatment of itaconate in tr-AMs. Moreover, the activation of NLRP3 inflammasome and its related pyroptosis was also augmented by itaconate in tr-AMs. By contrast, both dimethyl itaconate and 4-octyl itaconate, which are the derivates of itaconate, significantly reduced proinflammatory cytokines production and inflammasome activation in tr-AMs. These findings were also confirmed by genetic depletion of Irg1, which reduced the activation of NLRP3 inflammasome in tr-AMs. Importantly, genetic depletion of Irg1 protected mice against sepsis via inhibiting cytokines production in a mouse model of endotoxemia.

Conclusion: Itaconate has opposite effects on the activation of BMDMs and tr-AMs. The findings reveal a previously unrecognized function of itaconate in innate immunity and suggest caution for use of this molecule to treat inflammatory diseases.