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Cytokines of the IL‐17 family in psoriasis

Various immune cells and their messenger substances influence the development of psoriasis. Cytokines of the IL‐17 family are of particular importance. In addition to IL‐17A, which plays a central role in the pathogenesis of psoriasis, other subtypes of the IL‐17 family also have a proinflammatory effect. This review provides an up‐to‐date overview of the immunopathogenesis of psoriasis with regard to the six IL‐17 subtypes, in particular their physiological and pathogenic properties, as well as their significance for psoriasis therapy.


Introduction
Psoriasis can affect individuals of any age and often causes significant physical and psychological constraints [1]. Typical comorbid diseases of psoriasis are the metabolic syndrome, cardiovascular diseases, and psychological diseases [2]. The WHO describes psoriasis as one of the five serious non-infectious diseases that require special treatment and research [1]. Effective treatments that are specifically aimed at the pathogenesis of psoriasis have been developed in recent years and are included in the psoriasis guidelines [3][4][5][6].
In the past, Th17 cells of the adaptive immune system and the IL-23/IL-17 axis were the main focus of psoriasis research. According to new research, however, the relationships that occur in the immunopathogenesis of psoriasis are Summary Various immune cells and their messenger substances influence the development of psoriasis. Cytokines of the IL-17 family are of particular importance. In addition to IL-17A, which plays a central role in the pathogenesis of psoriasis, other subtypes of the IL-17 family also have a proinflammatory effect. This review provides an up-todate overview of the immunopathogenesis of psoriasis with regard to the six IL-17 subtypes, in particular their physiological and pathogenic properties, as well as their significance for psoriasis therapy.

Cytokines of the IL-17 family in psoriasis
much more complex. Studies have shown that various cell types of the innate immune system, including myeloid cells such as neutrophilic granulocytes, macrophages and mast cells, can produce IL-17A and IL-23 and can interact with cells of the adaptive immune response (such as Th17 and IL-17) that produce CD8 + T lymphocytes. Besides IL-17A, the other IL-17 cytokines are also important, as is determination of how they induce inflammation in psoriasis [7][8][9][10]. The IL-17 family has six subtypes: IL-17A, IL-17B, IL-17C,  IL-17 D, IL-17E (also known as IL-25) and IL-17F. The subtypes IL-17A and IL-17F have the highest homology (55 %) and are most often expressed together (co-expression). The sequences of IL-17B, IL-17D, and IL-17C overlap with IL-17A by about 23 % to 29 %, but the overlap with IL17-E is only 16 % [2]. IL-17 subtypes produce organ-specific pro-or anti-inflammatory responses via a total of six receptors [9] (Figure 1). Table 1 shows the IL-17 subtypes, their receptors, producing cells and effects on other cells, as well as their associations with various diseases [2].

IL-17A
IL-17A plays a central role in the pathogenesis of psoriasis. This was shown in several studies with the successful use of inhibiting antibodies [11]. It acts on non-hematopoietic cells, particularly epithelial cells, and plays an essential role in the immune response in neighboring organs. In the skin, IL-17A leads to increased proliferation and changed differentiation of keratinocytes, and induces antimicrobial peptides and chemokines. IL-17A also has a role in other inflammatory diseases. Elevated IL-17A concentrations have been measured in patients with multiple sclerosis (MS), rheumatoid arthritis and acute coronary syndrome that correlated with parameters of systemic inflammation [2,7].

IL-17F
IL-17F and IL-17A are coded at the same gene locus (6p12) and are regulated in a similar way. IL-17F can create heterodimers together with IL-17A. In psoriasis patients, IL-17F can be found in plaques at higher levels than in unaffected parts of the skin.
Studies have shown synergistic effects of IL-17F and IL-17A: unlike the inhibition of IL-17A alone, simultaneous inhibition of both cytokines leads to a significant increase in downregulation of inflammatory mediators in skin and joint fibroblasts [2,12]. IL-17F and IL-17A perform similar functions in bacterial or fungal infections [2,13,14].  Table 1 Overview of IL-17 subtypes with associated receptors, producing cells, effects on other cells as well as associations with diseases.

IL-17B
The function of IL-17B in psoriasis is largely unknown, and only weak expression has been described in psoriasis lesions [2]. IL-17B is not produced by activated T lymphocytes, but it has been found in neutrophil granulocytes, B-cells, neurons, stroma cells and colorectal epithelial cells. Synovial and pannus tissue in patients with rheumatoid arthritis (RA) has shown increased expression of IL-17B. IL-17B amplifies the effects of TNF-α in fibroblasts. This could be important for the immunogenesis of RA [15].

IL-17D
IL-17D is expressed in many cells and organs, but only weakly in immune cells such as lymphocytes and monocytes. IL-17D in vitro induced the production of IL-6, IL-8 and GM-CSF in endothelial cells. An inhibitory effect on the hematopoiesis of myeloid precursor cells was also detected [16]. Other studies have shown an association of IL-17D with viral and oncological diseases, particularly via recruitment of natural killer cells (NK cells). However, current data on IL-17D during tumor development are contradictory [17]. A deficiency in IL-17D led to a higher vulnerability to viruses in animal models.

IL-17C
IL-17C is not produced by T lymphocyte cells, but primarily by epithelial cells such as keratinocytes. A high concentration of IL-17C has been measured in human psoriasis plaques [18]. It can act as an autocrine stimulant for epithelial inflammation, particularly in combination with TNF-α. Overexpression of IL-17C in keratinocytes leads to psoriasiform dermatitis in mice [19]. IL-17C also leads to increased growth of sensory nerves. It was shown in a mouse model of herpes simplex infections of the skin that IL-17C can induce neuronal growth in a way similar to that of NGF (nerve growth factor) [18,20,21]. It has also been reported that depletion of IL-17C in mouse models of psoriasis and atopic dermatitis significantly reduces the inflammatory reaction. IL-17C therefore acts independently of T cells as an epithelial stimulant of immune reactions [19].

IL-17E (also known as IL-25)
IL-17E induces proliferation of keratinocytes and is able to activate innate immune cells. In psoriasis, IL-17E is strongly expressed by keratinocytes and activates specific subtypes of macrophages (M2 or tissue macrophages). In psoriasis lesions, IL-17E expression correlates positively with the number of neutrophil granulocytes and negatively with the number of T lymphocytes. This is surprising, since IL-17E was seen for a long time as a cytokine with a role in the Th2 immune response. An animal model of allergic asthma showed that inhibition of IL-17E by a neutralizing antibody resulted in a significant reduction of bronchial hyperreactivity, serum IgE concentration and histological signs of inflammation [22]. Similarly, IL-17E is also strongly expressed in atopic eczema [23,24].
Like IL-17C, IL-17E appears to amplify innate inflammatory processes in the skin, independently of the cells that contribute to the adaptive immune system [25].

Clinical aspects of IL-17 subtypes in psoriasis
Contrary to earlier notions of the pathogenesis of psoriasis, we now understand that there are other important inflammatory cycles apart from the IL-17A/IL-23 axis. On the one hand, the epithelial IL-17 cytokines IL-17C and IL-17E stimulate innate immune cells and the production of antimicrobial peptides. On the other hand, IL-17F leads to a pronounced increase of the IL-17A effects on epithelial cells. Animal experiments have shown the importance of these independent inflammatory cascades. For instance, the mouse model of psoriasis showed that when IL-17C is blocked, other immune mechanisms are stimulated that can allow the disease to persist [26]. This is a possible immunological explanation for the secondary loss of efficacy. Inhibition of a cytokine of the IL-17A/IL-23 axis could therefore modulate the inflammatory reaction and induce epithelial IL-17 cytokines such as IL-17C and IL-17E. However, there is currently no scientific evidence for this in humans.

Therapeutic consequences
Various biologics are currently approved for the treatment of psoriasis. Inhibition is focused on TNF-α, IL-12 (in combination with IL-23 inhibition) and the IL-17 subtypes IL-17A and IL-17F, or the subunit of the IL-17 receptor. The latter prevents an interaction of IL-17A, A/F, F, C, and E with the IL-17 receptor. Table 2 shows the biologics that are currently approved in the EU and that inhibit the effects of IL-17 subtypes or those of the IL-17A/IL-23 axis.
With regard to IL-17 subtypes and associated inflammatory cycles, it might be easier to stratify patients with psoriasis in the future. It is conceivable that some patients have a primarily adaptively driven psoriasis [7,27] that responds very well to IL-23 or IL-17A inhibition. From an immunological perspective, these could be patients who have only recently started to suffer from the disease, since chronic development and activation of other inflammatory cascades (such as epithelial IL-17 cytokines) has not yet occurred. Patients with stable psoriasis vulgaris without significant inflammation could also fall into this category. However, other patients might profit from the inhibition of several IL-17 cytokines. It is conceivable that these are patients who have suffered from psoriasis longer, have eczematized forms or possibly more inflammatory forms, since for them, activation of additional IL-17 cytokines (and other mediators such as IL-36) might sustain disease activity [7,27]. The stimulating effect of IL-17C on the growth of cutaneous nerves could also mean that patients with very itchy or inflammatory forms of psoriasis could benefit from the additional inhibition of IL-17C. Since IL-17E stimulates the inflammatory response of psoriasis on the one hand but also induces TH2 cytokines on the other hand, inhibition of IL-17E might positively affect accompanying allergic illnesses. Future studies must determine whether specific disease types can be defined and whether therapeutic decisions based on immunologic aspects can be made for selected psoriasis patients.