*Th17/IL-17, Immunometabolism and Psoriatic Disease: A Pathological Trifecta DOI: http://dx.doi.org/10.5772/intechopen.102633*

AMPK signaling promotes cell survival and also triggers autophagy (as an energypreserving mechanism) and mitochondrial biogenesis. HIF-1α, regulated by growth factor signals, oxygen levels, and reactive oxygen species (ROS), rapidly increases in an mTOR-dependent manner and binds to hypoxia response elements (HRE) located in the promoter region of various target genes, this leads to their activation by opening the chromatin structure. Thus, the mTOR/HIF-1α axis is associated with the initiation and development of a "pro-inflammatory" metabolic signature while activation of AMPK favors the generation of an anti-inflammatory/tolerogenic response.

These intertwined and reciprocal PI3K-Akt/mTORC/HIF-1α/c-MYC and LKB1– AMPK immunometabolic signaling networks crosstalk *via* direct reciprocal antagonisms, such as between mTORC1 and AMPK or Akt and LKB1 to regulate metabolism to meet context-specific and cell-specific functional needs [39]. These pathways are also mutually influenced by metabolites and nutrients generated as a consequence of these kinase dependent metabolic signaling, constituting 'bidirectional metabolic signalling' e.g. amino acid availability promoting mTORC1 signaling while low cellular glucose, low glutamine and elevated adenosine monophosphate (AMP) and adenosine diphosphate (ADP) concentrations can activate the AMPK pathway; metabolites generated from mitochondria-associated metabolism, i.e. α- ketoglutarate (α-KG), 2- hydroxyglutarate (2-HG) and acetyl-CoA, can influence transcription of a variety of genes lying in these immunometabolic signaling networks [42].

#### **Figure 2.**

*Signaling pathways regulating immunometabolism of immune cells. T-cell receptor ligation and CD28 costimulatory signals regulate immune-metabolic signaling pathways, i.e., mTORC1/C2 and LKB1-AMPK signaling. These signaling pathways are intertwined and crosstalk via direct reciprocal antagonism, i.e., AMPK directly inhibits mTORC1 while Akt suppresses LKB1 activity. (Left) Nutrient replete conditions activate PI3K-Akt/mTOR signaling that skew metabolic programming towards anabolism-associated processes such as glycolysis, fatty acid synthesis, and glutaminolysis supporting proliferation, differentiation, and heightened immune responses executed by effector immune cells (Th1, Th2, Th17 cells). (Right) Energy stress (increased AMP/ADP:ATP ratio), oxidative stress (increased reactive oxygen species, ROS), nutrient (glucose, glutamine) deprivation during malnutrition/starvation promotes LKB1-AMPK signaling, activating mitochondria-driven oxidative metabolism (citric acid cycle, oxidative phosphorylation, fatty acid oxidation), catabolic programs (autophagy/mitophagy), mitochondrial biogenesis, and inhibiting anabolic programs ultimately resulting in cellular quiescence.*

**Figure 2** explains how T- cells, under the influence of environmental signals, renew their metabolic equipment to employ metabolic pathways that regulate and propel function of these immune cells.
