Itaconate Promotes Inflammatory Responses in Tissue-Resident Alveolar Macrophages and Exacerbates Acute Lung Injury

Itaconate has been well recognized as an anti-inflammatory metabolite that displays therapeutic potential in multiple diseases, including inflammatory lung diseases. However, the immunomodulatory function of itaconate has been mainly derived from ex vivo-generated macrophages or macrophage cell lines, whereas its role in tissue-resident macrophages is still poorly understood. Here, we report that in contrast to its effects on bone marrow-derived macrophages (BMDMs), itaconate promotes the production of the proinflammatory cytokines interleukin-6 and interleukin-12 and augments the activation of the NLRP3 inflammasome in resident alveolar macrophages (AMs). Genetic deletion of immune-responsive gene-1 (IRG1) in AMs impairs itaconate-mediated activation of NLRP3, further demonstrating that endogenous itaconate is required for the optimal inflammatory response in AMs. Unlike natural itaconate, we find that the itaconate derivatives dimethyl itaconate (DI) and 4-octylitaconate (4OI) suppress the inflammatory response in AMs, indicating that itaconate and its derivatives act differentially. Mechanistically, the pro-inflammatory activity of itaconate in AMs is related to its inhibition of succinate dehydrogenase (SDH) rather than NRF2- and gasdermin D-driven responses. Importantly, intratracheal transfer of BMDMs into the airway reversed their responsiveness to itaconate, indicating an essential role of alveoli microenvironment in shaping macrophage immunometabolism. Using an acute lung injury model, we further demonstrate that itaconate promotes AM-mediated inflammatory responses in vivo and aggravates lung injury. Lastly, we confirm that natural itaconate promotes IL-1β production in human AMs upon its activation of the NLRP3 inflammasome. Taken together, our study unexpectedly demonstrates a pro-inflammatory role of itaconate in tissue-resident AMs, which not only challenges the conventional view that itaconate is an anti-inflammatory metabolite but also warrants further investigation before its clinical application.