Xu et al. found that IL-25 levels are increased in the psoriatic skin of mice specimens. In this model, knockout mice for the gene that encodes for IL-25 showed lower amounts of acanthosis, dermal thickness and immune cell infiltration, while injection of IL-25 alone led to the appearance of psoriatic lesions ^[1][12]. Senra et al. found that IL-25 leads to an accumulation of neutrophils led by macrophages in the site of injection of mice specimens. The psoriasis-like lesions disappeared after five days from the last injection, suggesting their acute role in the development of skin inflammation. The blockade of IL-25 through specific antibodies led to the result of turning off inflammation as well ^[2][13]. Borowczyk et al. found that IL-22, a cytokine mainly involved in epithelial and stromal cells, can upregulate the production of IL-25, which, as an autocrine effect, leads to proliferation and spikes in metabolic activity in vitro ^[3][14]. Senra et al. found that, in Pso lesions, levels of IL-25+ cells were higher than those found in control specimen, in particular in the lowermost levels (basal and supra-basal) of the epidermis and activating M2 macrophages to recruit neutrophils where the abscesses of Munro should develop (lowermost strata of epidermis) ^[4][15].

Chen et al. found that patients with moderate–severe psoriasis have both sera- and intra-epidermal levels of Il-33 higher than healthy controls and, in the same study, an Imiquimod induced Pso model in experimental mice was ameliorated by the injection of IL-33, suggesting the possible anti-inflammatory role of this cytokine ^[5][21]. Borsky et al. investigated the levels of various alarmins among which IL-33 in the serum of psoriatic patients and they found that its levels were significantly higher than in the controls but did not corelate with the severity of the disease ^[6][20]. Meephansan et al. proposed two branches of treatment in Pso patients, treated with methotrexate (MTX) or treated with narrow-band ultraviolet rays B (NB-UVB). In the group treated with MTX, levels of IL-33 were lower than before treatment; in contrast, after UVB therapy, levels increased. This led to contrasting results, since the shutting down of IL-33 by MTX led to an amelioration of the skin patches, but UVB therapy alone might produce a direct increase of this particular cytokine as a countereffect, without involving it in the pathogenetic process. The study did not suggest any other interpretations ^[7][19]. Raimondo et al. demonstrated that IL-33 from psoriatic plaques induces the release of a wide range of osteoclastogenic factors from the skin, such as RANKL, that promote monocyte differentiation in osteoclasts and other osteoclastogenic mediators that could act in a RANKL independent pathway. These results suggest a link between psoriatic cutaneous inflammation and the pathogenesis of psoriatic arthritis (PsA), thus explaining why in most cases Pso anticipates several decays in the onset of PsA ^[8][18].

Gago-Lopez et al. found that TSLP, in psoriasis, plays a wide variety of roles; TSLP enhances cell proliferation (via STAT5 pathway activation) and angiogenesis (via vascular endothelial growth factor production). In a murine model, antibodies directed against TSLP led to a positive response in terms of epidermal thickening and vascularization ^[9][38]. Tashiro et al., using cultures of HaCaT cells (immortalized keratinocytes), found that TSLP, in hypoxic conditions, presents reduced levels via the inactivation of its production stimulated by TNF-alpha, via HIF2 and HRE mechanisms (two products involved in the skin response to hypoxemia). It is the authors’ suggestion that targeting these two molecules could lead to lower levels of TSLP and the resolution of lesions both in Pso and AD ^[10][37]. Schaper et al. correlated the levels of TSLP from human skin samples derived from healthy controls, Pso patients and AD patients, noticing that both Pso and AD patients, but mostly Pso patients, presented higher levels of TSLP, especially the inflammation-related isoform rather than the basal one, via histamine release by hyper-active Th2 cells ^[11][34]. Segawa et al. developed a model using HaCaT cells again, demonstrating that EGFR is transactivated via TSLP by TNF-alpha; it is the author’s suggestion that, since anti-TNF drugs may produce many side effects (such as infections), targeting TSLP instead of TNF-alpha could provide the same results with greater benefits ^[12][35]. Chen et al., in a 2021 study, matched healthy controls to AD and Pso patients, showing that it is possible to differentiate two separate groups of Pso patients; the most interesting is the “early onset” group, with high levels of Th2 cells and a high TSLP response. The levels of TSLP were higher than those present in AD, suggesting that different subtypes of Pso could benefit from different types of treatment ^[13][39]. Desmet et al. suggested a novel approach in their study, in which they tried to use RNA interfering molecules, applied topically, to silence the production of several mRNAs among which the mRNA affecting TSLP release. As a result, levels of TSLP dropped, along with the other products, suggesting a possible future treatment for Pso in a 3D model skin ^[14][36].