| dc.description.abstract | Immunometabolism is a new branch of immunology that studies the interplay between
metabolism and immune cell activation. Mitochondria play a pivotal role in
immunometabolism as they host key metabolic processes such as the Krebs cycle and the
electron transport chain (ETC) operating oxidative phosphorylation (OXPHOS). This project
concerns two aspects of the role played by the mitochondria in metabolism – the anti-
inflammatory effect of the mitochondrial metabolite itaconate on eosinophils and the role of
mitochondrial glutathione (mtGSH) on the inflammatory responses in macrophages.
Itaconate is a metabolite produced from the Krebs cycle through cis-aconitate decarboxylation
by the enzyme aconitate decarboxylase (ACOD1) encoded by immunoresponsive gene 1
(IRG1). It is important in the context of immunometabolism due to its wide array of
immunomodulatory actions. 4-octyl itaconate (4-OI) is a cell-permeable derivative of itaconate
and similarly displays a variety of immunomodulatory roles. Through studies from itaconate
derivatives or from Irg1-deficient macrophages, several targets of itaconate have been
uncovered, such as NRF2, ATF3, and NLRP3. 4-OI and itaconate are also effective in
dampening inflammation in various animal disease models, including sepsis, psoriasis, and
ischemia-reperfusion injury (IRI). In asthma studies, itaconate and 4-OI have shown promise
in mitigating inflammation induced by allergens like ovalbumin (OVA) and house dust mite
(HDM). In my PhD project, I have found that 4-OI significantly reduces the production of
eosinophil-targeted chemokines in a variety of cell types, including lipopolysaccharide (LPS)-
and IL-4 stimulated macrophages, Th2 cells, and A549 respiratory epithelial cells. Notably,
NRF2-dependent mechanisms underlie the suppression of these chemokines in LPS-stimulated
macrophages. Furthermore, 4-OI interferes with IL-5 signaling, directly impacting eosinophil
differentiation. In a murine model of eosinophilic airway inflammation, 4-OI alleviates airway
resistance and reduces lung eosinophil recruitment, highlighting its therapeutic potential in
asthma management.
The ETC is situated in the mitochondrial inner membrane and consists of four major iron-sulfur
clusters (ISC)-containing protein complexes. Besides its role in ATP generation, the ETC also
influences immune responses through reactive oxygen species (ROS). Studies have linked
ETC-generated ROS to IL-1b and IL-10, and OXPHOS-produced ATP to NLRP3-mediated
IL-1b release. Itaconate has been shown to limit ROS via its inhibitory effect of succinate dehydrogenase (SDH), which might also impact on GSH, or mtGSH translocated by
SLC25A39 and SLC25A40. mtGSH neutralizes ROS and participates in ISC synthesis and is
likely linked to cytokine production. In the second part of this study, I investigated the role of
SLC25A40 in bone marrow-derived macrophages (BMDMs) activation.
I found that SLC25A40 is expressed in BMDMs and it stabilized ISC-containing proteins in
the ETC and protected cells from oxidative damage. Downregulation of SLC25A40
upregulated Gclc and Gclm, two genes encoding enzymes responsible for GSH synthesis,
implicating a compensatory mechanism. Furthermore, I linked SLC25A39 and SLC25A40 to
macrophage cytokine production. I showed that although the two proteins are functional
homologs, their knockdowns resulted in distinct cytokine effects. Specifically, SLC25A39
knockdown increased IL-10 and decreased IL-6, while SLC25A40 knockdown resulted in
decreases in IL-1b and IL-10.
Taken together, these findings add to the understanding of the complex role of mitochondria in
immunometabolism, providing evidence of itaconate derivatives targeting eosinophils in
asthma-like lung inflammation and a regulatory role for mtGSH in macrophage responses. My
results therefore underscore the therapeutic potential of targeting mitochondrial metabolites in
inflammatory diseases. | en |
