1. Pathophysiology of Psoriasis
A key feature of psoriasis is sustained inflammation leading to altered keratinocyte proliferation and differentiation. What triggers and maintains this inflammation is dysregulation of the immune system, both in its innate and in adaptive components, caused by the interplay between multiple genetic and environmental risk factors 
. Numerous cells and molecules are involved. Among these Th1, Th17, Th9, follicular Th (Tfh) and Th22 lymphocytes and their respective cytotoxic lymphocytes, Treg, γδT cells, dendritic cells, neutrophils, mast cells, NK and NKT cells, lymphoid innate cells (ILCs), keratinocytes, and IFN-α, INF-γ, IL-17, IL-22, IL-23, TNF-α, and numerous other dendritic cell-activating molecules, autoantigens, cytokines, chemokines play a role. An exhaustive discussion about all of them is beyond the scope of this section: the most crucial for “systematic repercussion” according to current evidence, will be described.
Following a chronologic line of discussion, dendritic cells are known to play a crucial role in the early stages of the disease. Although their mechanism of activation is still unclear, data show that antimicrobial peptides (AMPs), such as LL37, -defensins, S100 proteins, and cathelicidins, secreted by keratinocytes in response to damage, activate Toll-like receptors (TLRs) expressed by plasmacytoid dendritic cells (pDC), a particular type of dendritic cells that links innate and adaptive immunity 
. The activation of pDc is crucial. Triggered, they produce IFN-, which promotes the maturation of myeloid dendritic cells (mDC): a specific population of them (CD11c + CD1c- cells), under this stimulus, begins to produce molecules that have become new therapeutic targets: TNF-α, IL-23, and IL-12 
TNF-α is a pleiotropic molecule, meaning it is produced by a multitude of cells in addition to the DCs, and exerts its action on a multitude of cell types. It mainly induces in these the expression of adhesion molecules and secondary mediators. Noteworthy is that it stimulates the proliferation and differentiation of T lymphocytes, Th1, Th17, and Th22, which in turn will produce TNF-α, IL-17, IL-22, favoring initiation of a self-propelled cycle of inflammation. Essentially, this cytokine plays an indirect role in disease pathogenesis by promoting adaptive immune effects of the IL-23/IL-17 axis 
Activation of the IL-23/IL-1 axis, the focus on which has led to revolutionary targeted therapies, determines the amplification phase of the process and the tissue cellular response. Activated dendritic cells lead to massive lymphocyte infiltration and formation of DCs/T cell clusters, that facilitate the T-mediated response. The myeloid dendritic cells that infiltrate the dermis at this stage secrete IL-23, although, like TNF-α, it is not the only cell capable of doing so 
. IL-23 production stimulates IL-17 producing cells, which include Th17, Tc17, γδ T cells, ILC3, mast cells, and neutrophils. Noteworthy is that recent studies have revealed that most IL-17-producing cells consist of γδ T cells 
. The IL-17 cytokine family consists of 6 members, A–F, but only two have a pathogenetic role in psoriasis, IL17-A, and IL-17F. The former appears to have a stronger effect than the latter 
IL-17, in cooperation with other cytokines such as TNF-α and IL-22, induces the development of the psoriasis phenotype through tissue cell activation. The most relevant tissue response is provided by keratinocytes that, releasing chemokines and other pro-inflammatory molecules, such as CCL20 and IL-1 F9, sustain skin inflammation. Activation of the IL-23/17 axis is thus amplified by numerous mediators, and this determines the typical gene expression profile and histopathological picture of psoriasis 
An inflammatory cascade begins with IFN-γ and continues with TNF-α and IL-23 to end with IL-17, with progressive “disease-specificity”, so that IL-17 inhibitors, acting further downstream, have a more rapid onset of action 
. Next to these “main” mediators, we find some “collateral” ones. IL-22, for example, would be pathogenically more relevant in vitro than in vivo. The “IL-2/IFN-γ” axis, which was considered essential before the “IL-17-centric” model, deserves mention. Th1 lymphocytes activated by various mediators, including IL-12, produce IFN-γ which probably plays a role as an upstream cytokine in the IL-23/IL-17 axis, but its pharmacological inhibition has not produced satisfactory results 
. Other cells, such as neutrophils, vascular endothelium, and macrophages, also contribute to the pathogenesis of psoriasis, through the production of molecules such as VEGF, IL-17, IL-23 
. For what concerns psoriasis as immune-mediated systemic disease some questions still are pending: What do these processes occurring in the skin microenvironment have in common, and possibly connect, with the “systemic” ones? Which are the main pathogenetic drivers in psoriasis considered as a systemic inflammatory disease? Probably the best way to find answers is starting from the inflammatory pathway analysis rather than from the canonical point of view of clinical comorbidities.
3. TNA-α in Systemic Involvement in Psoriasis: And “Old but Gold” Pathogenetic Driver
TNF-α, is the historic molecule investigated first as a pathogenic driver in psoriasis, it has demonstrated an indirect role in skin pathophysiology, promoting the effects of the IL-23/IL-17 axis.
We can state that TNF-α is a less “skin-specific” molecule, than the IL-23/IL-17 axis, but that, according to the current evidence, in psoriasis considered as a systemic inflammatory disease remains a “hallmark”.
In psoriatic arthritis, for example, its expression is stimulated by IL-17, and thus TNF-α is located “downstream” of it. TNF-α promotes pathological bone resorption by inhibiting osteoblastogenesis via Dkk-1 and promoting osteoclastogenesis via RANKL 
. However, as is the case of pure cutaneous psoriasis, also the “IL-12/IFN-” axis has a pathogenic role in PsA, and TNF-α secretion, by Th1 cells, could be stimulated also in this sense. Thus, TNF-α could be located in the inflammatory cascade on the same level and upstream of IL-17 
. Although its position may seem collateral, “around” the IL-23/IL-17 axis, in reality, its role is crucial. TNF-α is equally expressed in the synovial tissue of psoriatic arthritis and rheumatoid arthritis 
. According to Belasco et al. IL-17 is expressed proportionally more in psoriatic skin than in the joint, whereas TNF-α expression is equivalent in the two 
. A question arises: can we consider IL-17 a “more cutaneous” molecule and TNF-α a “more arthropathic” molecule, in the context of psoriasis considered as a systemic disease, as suggested by the brilliant efficacy of TNF-α inhibitors in joint symptomatology and their superiority over IL-17/23 inhibitor, highlighted by studies?
The same is true for cardiometabolic involvement. In the process of atherosclerotic plaque formation, TNF-α plays a fundamental role. Armstrong et al. 
, noted how there might be two links between inflammation in psoriasis and atherogenesis. The first, mentioned above, is driven by the IL-23/17 axis, with a prominent role of IL-17, which is, according to the authors, involved in plaque instability. The second is, again, driven by the IL-12/INF-γ axis, with activation of Th1 cells producing TNF-α, which is more involved in plaque development. A study has demonstrated, through an interesting bioinformatics approach, that the dominant pro-inflammatory signals linking atherosclerosis and psoriasis are that of TNF-α and INF-γ 
. Globally, apart from psoriatic disease, TNF-α is known to induce insulin resistance both in vitro and in vivo, by reducing tyrosine kinase activity of the insulin receptor, and endothelial dysfunction, and it may contribute to altered cardiac remodeling after myocardial infarction. TNF-α exacerbates hepatic insulin resistance, resulting in increased FFA synthesis and decreased FFA oxidation, thereby promoting hepatic steatosis. It contributes to the pro-inflammatory state of obesity 
Numerous pieces of evidence estimate that in inflammatory bowel diseases (IBD), local TNF-α secretion induces not only tissue damage but also activation of the adaptive immune system, which perpetuates the inflammatory state resulting in systemic inflammation 
. Although clinical trials with nonselective anti-TNF-α antibodies completely failed, the role of TNF-α in the pathogenesis of multiple sclerosis is still widely debated 
4. Other Molecules, Other Cells: A Currently Collateral Role in Systemic Involvement of PsO
Studies have highlighted the role of other molecules and cells in the pathogenesis of psoriasis as an immune-mediated systemic inflammatory disease. According to the current evidence, however, they appear collateral or dependent on the systems considered above.
IL-22 has a role in the joint and cardiometabolic involvement of psoriasis, but is essentially dependent on the IL-23/IL-17 axis, since it has a primarily cooperative action with IL-17 
. Moreover, the strategy of blocking IL-22 has proven to be not effective in treating psoriasis 
. L-1β induces dermal γδ T cell proliferation and IL-17 production in mice. In addition, IL-1β stimulates keratinocytes to secrete chemokines that preferentially chemoattract peripheral CD27- CCR6 + IL-17 capable of producing γδ T cells (γδT17) 
Adipokines are cytokines produced by adipose tissue, which have functions in the regulation of metabolic functions, such as glucose and lipid metabolism, inflammation, and vascular homeostasis. They have been implicated in cardiovascular involvement in psoriasis. According to a recent review on the subject by Lynch et al. 
, studies on adiponectin are contradictory regarding its pattern in PsO, and prospective controlled studies are needed to clarify their relationship. High levels of pro-inflammatory cytokines resistin and leptin have been detected and correlate with disease severity, but rather than a pathogenic role they may constitute markers of disease.
Vitamin D is a regulator of keratinocyte differentiation, and low levels of vitamin D have been associated with metabolic syndrome and increased cardiovascular risk. However, studies in this regard suggest a need to treat low serum levels of vitamin D in the course of psoriasis, rather than a central pathogenic role of vitamin D in psoriasis as a systemic disease 
Communication between neutrophils and macrophages is crucial in any inflammatory response and especially that underlying atherosclerosis 
, and NETosis, or the ability of neutrophils to expel cytosolic and nuclear material forming extracellular traps that ensnare extracellular microbes, has been proposed to have a role in atherosclerosis as well as psoriasis, but these findings seem too general 
Further studies are certainly needed to further investigate the role in the systemic involvement of psoriasis of other cells and molecules than IL-17, IL-23, and TNF-α, which currently seem “more central”.