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

pathogenicity; has been recognized as a critical molecular switch of Th17 cell's function (pathogenic versus non-pathogenic phenotype) though it does not affect Th17 differentiation [59]. Loss of CD5L transforms non-pathogenic Th17 cells into disease-inducing pathogenic ones by modulating intracellular lipidome saturation (PUFA versus SFA lipid balance) and by elevating intracellular free cholesterol, thereby regulating the quality and/or quantity of available ligands for RORγt [13]. PUFA regulates the ligand-dependent function of RORγt: in the absence of CD5L/PUFA (**Figure 5**), RORγt binding to the *IL-17* and *IL-23* loci is increased leading to transactivation of both these genes, while binding to *IL-10* locus is decreased leading to its downregulation. Thus, the balance of lipid saturation contributes to CD5L-dependent regulation of Th17 cells by regulating the RORγt genomic binding and Th17-cell transcriptome.

Dietary LCFAs enhance Th1 and Th17 cell differentiation and also alter the composition of the gut microbiome whereas SCFAs (derived from diet/intestine/microbiota) promote Treg cell formation, demonstrating unique phenotypes driven by different fatty acids [60].

The same glycolytic-lipogenic-glutaminolytic metabolic axis co-ordinated by mTORC1/HIF-1α, plays an equally important role in controlling the generation as well as the "pathogenicity" of Th17 cells. These findings highlight how the generation of Tregs/non-pathogenic Th17/pathogenic Th17 cells is tightly linked to their metabolic state, offering potential new targets for the regulation of these two reciprocally regulated T cell subsets (**Table 2**). Thus, it is quite clear that the generation of Th17 cells is entwined with complex and intricate intracellular metabolic adaptations.


#### **Table 2.**

*Comprehensive list of metabolic changes determining Th17 cell fate.*

#### **5.4 Crosstalk between IL-17 and cellular immunometabolism in psoriasis**

IL-17 has the potential to temper the cellular metabolism in a variety of ways. IL-17 has already been shown to regulate metabolism in psoriatic keratinocytes by reprogramming the urea cycle resulting in excessive polyamine generation that facilitates self-RNA sensing by immune cells independent of RNA-binding proteins LL37 and HNRNPA1 (the proven autoantigens) ultimately leading to amplification of inflammatory circuits [61, 62].

IL-17 also induces intracellular cholesterol accumulation that facilitates NF-κB mediated up-regulation of CCL20, IL-8 and S100A7 expression in keratinocytes thereby further intensifying IL-17A induced psoriatic inflammation [63]. This highlights that how IL-17-induced metabolic alterations can actively participate in eliciting infiltration and activation of innate and adaptive immune cells and keratinocyte hyperproliferation leading to sustained inflammatory dermatoses.

#### *5.4.1 Therapeutics in psoriasis*

Depending upon disease severity (based on PASI scores), topical therapy (vitamin analogues, tars, corticosteroids, dithranol, and retinoids), phototherapy (UV-B or PUV-A), and systemic therapy are considered for treatment of psoriasis. Systemic therapeutic agents used in psoriasis include methotrexate, cyclosporine, retinoids and biologics including etanercept, adalimumab, efalizumab, and alefacept. Other approved biologics for psoriasis include anti-IL-23 antibodies (ustekinumab, guselkumab, tildrakizumab, mirikizumab, risankizumab) targeting only IL-23/IL-17 axis and anti-IL-17 antibodies including anti-IL-17A agents (ixekizumab and secukinumab), anti-IL-17 receptor molecules (brodalumab); or drugs targeting both IL-17A and IL-17F (bimekizumab) [64]. These antibodies have shown promising results in the treatment of psoriasis with IL-17 blockers showing much quicker clinical efficacy resulting in a 50% decline in PASI scores as early as 1.8 weeks as compared to IL-23 blockers [65, 66].

To decrease toxicity and enhance efficacy, a few anti-metabolites are currently being repurposed and investigated as potential therapeutic agents for the management of psoriasis [67]. Metformin, an antidiabetic drug, has the potential to exert an antipsoriatic effect via. AMPK activation [68]. Simvastatin, an HMG-CoA reductase inhibitor, in combination with steroids, has demonstrated positive clinical outcomes in psoriatic patients in terms of improved PASI and dermatological life quality index [69]. These examples provide insight to clinicians for investigating the safety and efficacy of existing anti-metabolite drugs to reposition them as effective psoriasis therapeutic agents.
