Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate.
#COCKTAIL FOR MAC 9.3.1 ACTIVATOR#
Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Here, Martínez-Reyes and Chandel review key metabolites and describe their effects on processes involved in physiology and disease including chromatin dynamics, immunity, and hypoxia. Mitochondrial metabolites contribute to more than biosynthesis, and it is clear that they influence multiple cellular functions in a variety of ways. We will focus on how these metabolites mediated signaling can affect physiology and disease. This review summarizes the mechanisms by which the abundance of different TCA cycle metabolites controls cellular function and fate in different contexts. Recent evidence confers a new role for TCA cycle intermediates, generally thought to be important for biosynthetic purposes, as signaling molecules with functions controlling chromatin modifications, DNA methylation, the hypoxic response, and immunity. Multiple mechanisms contribute to communicate mitochondrial fitness to the rest of the cell. Mitochondria are signaling organelles that regulate a wide variety of cellular functions and can dictate cell fate. We suggest that a type I IFN-mitochondrial feedback loop controls macrophage responses to mycobacteria and that this could contribute to pathogenesis across a range of diseases. We confirm that type I IFN acts upstream of mitochondrial damage using macrophages lacking the protein STING. IFNβ itself restrains the glycolytic shift of inflammatory macrophages and initiates mitochondrial stress. Macrophages lacking the type I IFN receptor (IFNAR) maintain glycolytic flux and mitochondrial function during Mtb infection in vitro and in vivo. We find that type I interferon (IFN) signaling correlates with the decreased glycolysis and mitochondrial damage that is induced by live, but not killed, Mtb. In this study, we characterize the metabolic and transcriptional responses of murine macrophages to Mycobacterium tuberculosis (Mtb) in order to disentangle the underlying mechanisms. Metabolic reprogramming powers and polarizes macrophage functions, but the nature and regulation of this response during infection with pathogens remain controversial. These results reveal that IFNβ modulates macrophage activation and polarization through control of the cellular α-ketoglutarate/succinate ratio. The suppressive effects of IFNβ on JMJD3-IRF4-dependent responses, including M2 polarization and GM-CSF-induced inflammatory pain, were reversed by supplementation with α-ketoglutarate. We show that by lowering the α-ketoglutarate/succinate ratio, IFNβ potently blocks the JMJD3-IRF4-dependent pathway in GM-CSF and IL-4 activated macrophages. Combined, we identify that IFNβ controls the cellular α-ketoglutarate/succinate ratio.
IFNβ also increased the flux of glutamine-derived carbon into the tricarboxylic acid cycle to boost succinate levels. We find that IFNβ simultaneously increased the expression of immune-responsive gene 1 and itaconate production while inhibiting isocitrate dehydrogenase activity and restricting α-ketoglutarate accumulation. Here we explore the impact of type I interferon (IFNβ) on macrophage metabolism and its broader impact on cytokine signaling pathways. Metabolic adaptations can directly influence the scope and scale of macrophage activation and polarization.
0 kommentar(er)
