**4. Immunometabolism**

A multifaceted, complex regulation of immune networks both depend on, and influences, cellular and local/systemic metabolic environment. This intricate, dynamic interplay between immunity and metabolism, i.e., "immunometabolism" outlines the metabolic patterning of immune cells and maintains metabolic homeostasis (local/systemic) but can also result in metabolic disorders dominated by deranged immune cells [33, 34]. In other words, immunometabolism can be defined as a molecular and biochemical intertwining of metabolism and immunology in all organisms that accounts for the physiological functioning of the immune system in different metabolic conditions in health and disease [35]. Immune response/ inflammation can modulate cellular and tissue/systemic metabolism and viceversa. Therefore, there are 2 dimensions to immunometabolism: the first is "cellular immunometabolism", which includes the intracellular metabolism of a variety of immune cells under different states of activation, polarization, proliferation, and

differentiation and the 2nd dimension is tissue/systemic immunometabolism, which explores the influences of immune cells and their products on local and systemic metabolism across various settings/organs [36]. Thus, the immune system, which can be prompted by the metabolic status of the body can, in turn, have significant consequences on cellular and systemic metabolic homeostasis or disarray.

We will cover these two dimensions of psoriasis-associated immune-metabolism separately:

### A. Cellular immunometabolism

The impact of changes in major cellular metabolic pathways on differentiation of Th17 cells, the "signature" cells in psoriasis.

B. Tissue/systemic immunometabolism

The influence of the resultant Th17 response on metabolism across various tissues or organs, especially white adipose tissue (visceral and cutaneous) culminating in metabolic syndrome and other psoriasis-associated co-morbidities.

Before delving deeper into these, we will brush up on immune-metabolic signaling pathways and discuss a basic outline of the major metabolic pathways used by immune cells.

#### **4.1 Metabolic regulation of immune cells**

Innate as well as adaptive immune cells have immense malleability to actively respond to different metabolic demands and diverse metabolic microenvironments *via* dynamic regulation of intracellular metabolism in health and disease [37]. Extracellular/environmental cues such as partial pressure of oxygen, oxidative stress, organ-specific pH, nutrient gradients, and disease-dependent fluctuations of the metabolic environment, can shift the metabolic homeostasis of immune cells. Body fluids such as blood and lymph, and the nervous system represent communication conduits for inter-organ coordination; distal communication is executed by the usual messenger molecules (hormones, neurotrophic peptides, cytokines, chemokines, and metabolites) while organelle communication within the cell is carried out by intracellular, spatially organized metabolic processes [38]. These communication networks at various levels orchestrate and harmonize responses to environmental cues/immunological challenges. The signals are sensed by metabolic serine/threonine kinases *viz*. phosphoinositide 3 kinase (PI3K)—protein kinase A, G and C (AGC) kinases (Akt), mechanistic/mammalian target of rapamycin (mTOR) C1/C2, and energy stress pathway kinases, *i.e.,* liver kinase (LK) B1–5′AMP-activated protein kinase (AMPK) in co-ordination with metabolic transcription factors like hypoxia-inducible factor (HIF)-1α, cellular-myelocytomatosis oncogene (c-MYC) and associated nutrient signaling networks. These integrate available environmental information to synchronize cellular proliferation by metabolic revamping [39]. mTOR has been recognized as a molecular orchestrator of immune cell metabolism and catalyzes aerobic glycolysis and anabolic metabolism after stimulation by proinflammatory agents [40]. AMPK, a sensitive radar for decreased cellular nutrients and energy, stimulates catabolic pathways by impeding mTORC1 activity and primarily facilitates T cell adaptation to situations of low nutrient availability as seen during malnutrition, starvation and in hypoxic microenvironments associated with chronic inflammatory conditions [41].
