Dataset Information

Adenylate kinase 4 Promotes the expression of Inflammatory Genes in Macrophages via Hif-1a

ABSTRACT: Macrophages comprise the first line of defense against various pathogens. Classically activated macrophages (M1), induced by IFNg and LPS, express a high level of inflammatory cytokines and contribute to inflammatory processes. By contrast, alternatively activated macrophages (M2) are induced by IL-4/IL-13, produce IL-10, and display anti-inflammatory activity. Adenylate kinase 4 (Αk4), an enzyme that transfers phosphate group among ATP/GTP, AMP, and ADP, is a key modulator of ATP and is involved in maintaining the homeostasis of cellular nucleotides which is essential for the function of cells. However, its role in regulating the function of macrophages is not fully understood. Here we report that the expression of Ak4 is induced in M1 but not M2 macrophages. Suppressing the expression of Ak4 in M1 macrophages with shRNA enhances the production of ATP. RNA-seq analysis identifies several inflammation-related genes, including Il1b, Il6, Tnfa, Nos2 and Hif1a, as downstream targets of Ak4. We further demonstrate that Ak4 and Hif1a form a positive feedback loop in sustaining the expression of the inflammation-related genes. Our data depict a potential mechanism linking energy consumption and inflammation in macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE143302 | GEO | 2021/04/07

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Dataset Information

Adenylate kinase 4 Promotes the expression of Inflammatory Genes in Macrophages via Hif-1a

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets