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SLC25A33-mediated mitochondrial DNA synthesis plays a critical role in the inflammatory response of M1 macrophages by contributing to mitochondrial ROS and VDAC oligomerization

ABSTRACT: M1 macrophage polarization is modulated by the release of mitochondrial DNA (mtDNA) and subsequent its inflammatory response is augmented by production of mitochondrial reactive oxygen species (mtROS). The pyrimidine-transporting carrier SLC25A33 is located in the mitochondrial inner membrane and has been linked to mtDNA synthesis, but the role of SLC25A33 in inflammatory response of M1 macrophage remains unclear. Here, we elucidate the regulatory mechanisms responsible for up-regulation of SLC25A33 during M1 macrophage polarization and SLC25A33-mediated mtROS production and inflammatory response. Our findings reveal that expression of SLC25A33 was significantly elevated in CD14+ monocytes derived from a patient with sepsis and LPS/IFN-γ-stimulated PMs. We demonstrate that SLC25A33 is upregulated by ATF4 through the MyD88-PI3K-mTORC1 pathway in LPS/IFN-γ-stimulated PMs. Furthermore, SLC25A33 enhanced mtDNA synthesis and its release into the cytosol, facilitated by mtROS-mediated VDAC oligomer formation, thereby contributing to activation of the cGAS-STING inflammatory pathway. Conversely, SLC25A33 knockdown and pyridoxal 5'-phosphate treatment mitigate mtDNA release and reduce M1 polarization and associated inflammatory responses. These findings were consistent across in vitro and in vivo sepsis models, as well as in septic patients with liver abscess. Our findings underscore the significant role of SLC25A33 in inflammation, suggesting that targeting of SLC25A33 could represent a promising therapeutic strategy for managing M1 macrophage-mediated inflammatory diseases, including sepsis.

ORGANISM(S): Mus musculus

PROVIDER: GSE280094 | GEO | 2024/10/28

REPOSITORIES: GEO

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Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

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SLC25A33-mediated mitochondrial DNA synthesis plays a critical role in the inflammatory response of M1 macrophages by contributing to mitochondrial ROS and VDAC oligomerization

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