**6.1 Adipose tissue and immune-metabolism: an interesting interlink**

Besides metabolically active parenchymal adipocytes and preadipocytes, adipose tissue is also comprised of a diverse and malleable immune-landscape comprising both innate and adaptive immunocytes residing in special adipose niches [72]. This diversity of T cell pools in adipose tissue is the result of intracellular metabolic alterations that in turn influence systemic metabolism in innumerable ways. Adipose tissueresident immune cells include T cells, B cells, macrophages, and dendritic cell subsets and other unconventional lymphocyte subtypes *viz*. invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, γδ T cells and innate lymphoid cells 2 (ILCs) with either stimulating or regulatory roles under different physiological or pathological conditions [73]. All these immunocytes work in close co-operation with preadipocytes, adipocytes, endothelial cells and stromal cells (fibroblasts) to maintain the immune and metabolic homeostasis of adipose tissue, providing a steady environment to maintain the normal systemic metabolism of an organism [74]. Extremely heterogeneous mesenchymal stromal cells (five subtypes numbered 1–5, defined by single-cell transcriptomics analysis and cytofluorimetric assessment of marker expression) in visceral white adipose tissue have been characterized as key orchestrators of metabolic-immunologic cross-talk by their ability to balance *'immunocyte'* numbers through secretion of IL-33 (subtypes 1–3) and *'adipocyte'* numbers/ activities through regulation of adipocyte precursors (subtypes 4 and 5) [75]. The stromal cell-derived IL-33, a mechanosensitive chemokine, dampens aberrant inflammation by increasing Treg numbers. IL-33 has been recently shown to induce mitochondrial rewiring, thereby promoting differentiation of alternatively activated macrophages finally leading to resolution of inflammation [76]. Taken together, tight and well-balanced cooperation and coordination exist between parenchymal-stromalimmune cell populations that ultimately regulate adipose tissue homeostasis.

Intradermal adipocytes residing in "superficial subcutaneous adipose tissue" or "dermal white adipose tissue" of psoriatic skin secrete monocyte chemoattractant protein-1 (MCP-1) favoring macrophage recruitment via the C-C chemokine receptor 2 (CCR2) pathway and also release high levels of antimicrobial peptides, cathelicidin, contributing to the pathophysiology of psoriasis [77].

### *6.1.1 Adipocytokines and cytokines released by adipocytes*

Adipocytes participate in the regulation of the immune system *via* secretion of various cytokines – including IL-6 – and adipocytokines such as adiponectin and leptin. IL-6, an obligatory pro-inflammatory cytokine, drives naïve CD4+ T cells differentiation into Th17 lineage, and in association with IL-17A, regulates the differentiation of adipocytes and their capacity to secrete adipocytokines (especially leptin) and chemokines [78].

Adiponectin is an insulin-sensitizing anti-inflammatory adipocytokine that corrects insulin resistance and obesity-induced NAFLD (21). Leptin is a critical hormonal regulator of metabolism and an important signaling transducer that activates JAK2 kinase causing tyrosine phosphorylation of various downstream signaling proteins, e.g., STAT3, SHP2, IRS2, and PI3K, thereby regulating transcription of genes essential for energy intake and lipid metabolism [79, 80]. Leptin also affects various immune cells including dendritic cells (DCs), neutrophils, NK cells, T and B cells, through surface leptin receptors and regulates a variety of cellular biological processes involving chemokinesis, chemotactic responsiveness, cell migration, proliferation, cell survival (delayed apoptosis) and pro-inflammatory cytokine production [81, 82]. Resistin, another cytokine is also known as an adipose tissue-specific secretory factor (ADSF) also has the pro-inflammatory potential [83].

A disturbed balance of pro-inflammatory and anti-inflammatory cytokines and adipocytokines (hormones) can cause chronic adipose tissue inflammation resulting in obesity and associated metabolic complications.

#### **6.2 Obesity, systemic immunometabolism and psoriasis**

Obesity (fat and weight gain/body mass index (BMI) ≥ 35 kg/m2 /increased abdominal fat mass) resulting from adipose tissue expansion and adipocyte hypertrophy, is a state of chronic systemic low-grade inflammation that accelerates obesity-related insulin resistance (IR), leading to the development of the metabolic syndrome, including diabetes mellitus (DM). Obesity increases the body's vulnerability to a variety of immune diseases, such as psoriasis, by abnormally altering the whole biology of adipose tissue including stromal-driven regulation of immunocyte and adipocyte numbers. Obesity evokes extensive remodeling of adipose tissue morphology and function with alterations of both immune as well as stromal cell landscapes resulting in metabolic and/or immunologic aberrancies [84]. The number of pro-inflammatory immunocytes *viz*. CD8+ T cells, M1 macrophages, neutrophils, mast cells, and γδ T cells increases while the proportions of tolerogenic/ immunosuppressive cells *viz*. Tregs, regulatory B cells (B regs), eosinophils, iNKT cells, alternatively activated macrophages and type 2 ILCs (copiously producing anti-inflammatory cytokines IL-10, IL-15, IL-2, IL-5, and IL-25) are either decreased or have impaired functional capacity. Various studies have already shown a strong "dose-dependent" relationship between PASI scores and obesity with improvement in disease severity as a result of weight loss in psoriatic patients [85, 86].

Obesity has been postulated to worsen psoriasis *via.* Its effect on the Treg/Th17 axis through various metabolites, adipocytokines like leptin and pro-inflammatory cytokines like IL-6, released by inflamed adipocytes [72, 87, 88] for example, higher leptin and resistin concentrations have been observed in obese, psoriatic patients [89, 90].

Adiponectin plays a crucial role in controlling psoriasiform dermatosis by reducing Th17 cell differentiation, restraining glycolysis in an AMPK dependent fashion, thus tightly regulating their nutritional demands and metabolic function [91–93]. Psoriasis patients with or without metabolic abnormalities exhibit significant hypoadiponectinemia (negatively corelated with psoriasis area severity index, PASI) and hyperleptinemia with leptin resistance (positively corelated with PASI), that contribute to the development of the metabolic syndrome.

The pro-inflammatory cytokine IL-17, a potential linker between metabolic syndrome and psoriasis, causes adipose tissue inflammation by mediating important interactions between adipose tissue and the immune system, leading to IR (the key

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

component of metabolic syndrome) finally manifesting as obesity, DM, hypertension, NAFLD, and hyperlipidemia [21].

Thus, it can be inferred that obesity-driven immune and stromal landscape alterations in adipose tissue, in turn leading to disturbances in systemic metabolism might enhance Th17 differentiation and effector function, consequently leading to increased severity of psoriasis.

#### **6.3 Nutritional metabolism and psoriasis**

Beyond the adipose tissue, the diet or nutritional status, a.k.a. nutritional metabolism, also has a profound impact on the immune system by influencing the immune cell metabolic parameters; malnutrition is clearly associated with diminished immune function whereas a "Western" lifestyle/nutritional pattern rich in calories, fat, and salt, leads to a low-grade systemic inflammation thereby predisposing individuals to a variety of autoimmune diseases associated with metabolic complications, including psoriasis. Diet-associated obesity by increasing availability of extracellular lipids revamps cellular metabolism of innate as well as adaptive immune cells [94]. It is quite tantalizing to consider dietary interventions like fasting-mimicking diets and diets low in salt and calories re-stabilizing the immune-metabolism in psoriasis patients, potentially serving as viable substitutes or adjuvants to drugs directly targeting cellular metabolism.

Understanding the relationship between nutrition and metabolism and its impact on cellular/systemic immunometabolism in psoriasis is important to develop novel therapeutic strategies.
