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“Anti-inflammatory” enzyme plays proinflammatory role in sepsis

Scientists have discovered that the enzyme aconitate decarboxylase 1 (ACOD1) is not an anti-inflammatory mediator in sepsis. In the presence of bacterial toxins, it is involved in the cytokine storm and inflammatory signaling in monocytes and macrophages, becoming a potential therapeutic target against the infection.

This proinflammatory role is the opposite of ACOD1's previously known role in myeloid cells.

Here, ACOD1 (also known as immune-responsive gene 1 protein or IRG1) favors itaconate production to inhibit bacterial innate immunity. Itaconate can activate the anti-inflammatory response.

However, ACOD1's role in sepsis is different. A group of researchers of the University of Texas Southwestern Medical Center (UTSW) has demonstrated that ACOD1 participated in the proinflammatory response by activating a cytokine storm through the tumor necrosis factor (TNF) signaling pathway independently of itaconate.

"We found that many infection-related inflammatory pathways were significantly shut down or downregulated, rather than significantly upregulated, following ACOD1 deletion," Daolin Tang, associate professor of surgery and director of the center for damage-associated molecular patterns (DAMP) biology at UTSW, told BioWorld Science. "This finding overturns the traditional understanding of ACOD1's anti-inflammatory function," he said. Tang is the senior author of the study, published in the August 24, 2022, issue of Science Translational Medicine.

This process was triggered by the phosphorylation of the enzyme cyclin-dependent kinase 2 (CDK2), which takes part in the activation of mitogen-activated protein kinase 8 (MAPK8) through receptor for activated C kinase 1 (RACK1). This resulted in JUN-dependent transcription of ACOD1, which once activated, accumulated in cells, induced the cytokine storm, and promoted inflammation.

To evaluate the original hypothesis in sepsis, the anti-inflammatory role of ACOD1, scientists compared the effect of its deletion on immune signaling pathways using whole-genome sequencing technology of THP1 cells, a cellular lineage derived from a patient with acute monocytic leukemia.

Deletion of CDK2, ACOD1, or administration of the drug dinaciclib (a CDK inhibitor) decreased the cytokine storm, prevented sepsis, and improved survival in mice infected intraperitoneally with the Gram-negative bacteria Escherichia coli or the Gram-positive Streptococcus pneumoniae. These pathogens are the main responsible for septic death in humans. In animal models, administration of dinaciclib improved survival.

In addition, the authors have observed that in a cohort of 40 people with bacterial sepsis, the expression of the CDK2-ACOD1 axis was associated with the severity of disease, which suggests that drugs such as dinaciclib could improve outcomes against these serious infections.

Data confirm that ACOD1 participates in an important biochemical pathway for tumor development, along with CDK2 and TNF. Dinaciclib has orphan drug designation by the FDA for some cancers.

A role for cancer drugs?

"Sepsis and cancer share some common pathological features in immune dysfunction and signal transduction. Thus, we need to consider whether certain anticancer drugs can be used to design clinical trials to treat patients with sepsis," Tang remarked.

Other anticancer drugs such as camptothecin (which inhibits topoisomerase I) or LDK-378, a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, are also good candidates against sepsis in preclinical models.

"Our current study shows that ACOD1 exerts proinflammatory effects depending on the complex it forms with GIMAP7 protein. However, the structural basis for their interaction remains undetermined," Tang said.

The binding of ACOD1 to GIMAP7 is necessary to produce TNF. This is one of the functions of ACOD1, apart from its involvement in the production of itaconate, which is another of its functions. Although itaconate is anti-inflammatory and antibacterial, in some cases it provokes the replication of pathogens or the production of cytokines. GIMAPs, however, are expressed on immune cells, where they mediate TNF production and signaling, and the inflammatory response.Understanding this interaction may lead to the development of new inhibitors that specifically target the proinflammatory function of ACOD1. "This will also minimize the side effects of applying ACOD1 inhibition strategies in lethal infections," he concluded.

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