Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes

Complements and neutrophils are two key players of the innate immune system that are widely implicated as drivers of severe COVID-19 pathogenesis, as evident by the direct correlation of respiratory failure and mortality with elevated levels of terminal complement complex C5b-9 and neutrophils. In this study, we identified a feed-forward loop between complements and neutrophils that could amplify and perpetuate the cytokine storm seen in severe SARS-CoV-2–infected patients. We observed for the first time that the terminal complement activation complex C5b-9 directly triggered neutrophil extracellular trap (NET) release and interleukin (IL)-17 production by neutrophils. This is also the first report that the production of NETs and IL-17 induced by C5b-9 assembly on neutrophils could be abrogated by mesenchymal stem cell (MSC) exosomes. Neutralizing anti-CD59 antibodies abolished this abrogation. Based on our findings, we hypothesize that MSC exosomes could alleviate the immune dysregulation in acute respiratory failure, such as that observed in severe COVID-19 patients, by inhibiting complement activation through exosomal CD59, thereby disrupting the feed-forward loop between complements and neutrophils to inhibit the amplification and perpetuation of inflammation during SARS-CoV-2 infection.     

Neutrophil chemoattractant and IL-1-like activity in samples from psoriatic skin lesions. Further characterization

The IL-1-like neutrophil chemoattractant activity previously reported by us to be present in the stratum corneum of psoriatic skin lesions has now been characterized further. Aqueous extracts of stratum corneum samples from psoriatic lesions and from the heels of normal volunteers were ultrafiltered to yield 10- to 30-kDa fractions. The ultrafiltered psoriatic preparations consistently contained greater neutrophil chemokinetic activity than the normal heel preparations, but in contrast the latter contained markedly greater IL-1 activity than the former. Successive chromatographic purification of psoriatic lesional stratum corneum extracts showed that the neutrophil chemokinetic material previously reported to co-elute with IL-1 activity on reversed phase HPLC, but to be distinct from C5a des arg, could now be separated by anion exchange HPLC into at least four different chemokinetic compounds that were also resolved from the IL-1 activity. The reversed phase HPLC-purified chemokinetic material from psoriatic stratum corneum was also active in a neutrophil chemotaxis assay. These findings show that samples from psoriatic skin lesions contain a group of novel 10- to 30-kDa neutrophil chemoattractant compounds that are distinct from both C5a des arg and IL-1. The contrasting neutrophil chemokinetic and IL-1 activities in psoriatic lesional and normal heel stratum corneum preparations support the finding that the two activities are produced by different compounds. These neutrophil chemoattractant and IL-1-like compounds may be of pathogenic importance in inflammatory skin disease.     

Physical characterization of the stratum corneum of an in vitro psoriatic skin model by ATR-FTIR and Raman spectroscopies

The stratum corneum is an important permeability barrier for the skin. The disorganization of the skin protective barrier characterizes some skin diseases such as psoriasis. Indeed, psoriatic skin is known to be more permeable than normal human skin. An in vitro human skin substitute may be obtained by the auto-assembly method. This method was adapted to produce psoriatic substitutes. FTIR spectroscopy is a well-established method to evaluate the order of hydrocarbon chains in terms of population of trans and gauche conformers. Using ATR-FTIR, we have compared the physicochemical properties of the stratum corneum in skin models derived from uninvolved and involved psoriatic cells with those derived from normal cells. Our results suggest that the stratum corneum of involved psoriatic skin substitutes is less organized than that of normal skin substitutes. Also, it seems that the properties of uninvolved psoriatic skin may vary with seriousness of the disease. The development of a new psoriatic skin model would be helpful in the design of new treatments and to increase the understanding of the mechanisms of this pathology.     

Topical antioxidant vitamins C and E prevent UVB-radiation-induced peroxidation of eicosapentaenoic acid in pig skin

Eicosapentaenoic acid protects against UV-radiation-induced immunosuppression and photocarcinogenesis, but it is also prone to oxidative degradation, which may reduce or abolish its beneficial effects. The protective effect of topically applied vitamin E, vitamin C, or both against UVB-radiation-induced lipid peroxidation in the presence of eicosapentaenoic acid was investigated using an ex vivo pig skin model. Changes in the bioavailability of both antioxidants induced by UV radiation were studied in different skin compartments. The UVB-radiation dose used (25 kJ/m2) was similar to that required to induce immunosuppression in BALB/c mice. Exposure of pig skin with an epidermal eicosapentaenoic acid content of 1.0 +/- 0.3 mol% to UVB radiation resulted in an 85% increase of epidermal lipid peroxidation (P < 0.005). Topical application of vitamin E or vitamin C 60 min prior to UVB irradiation resulted in a major increase in both antioxidants in the stratum corneum and viable epidermis (P < 0.05). Vitamin E and vitamin C completely protected against UVB-radiation-induced lipid peroxidation (P < 0.005), but compared to vitamin E, a 500-fold higher vitamin C dose was needed. UVB irradiation induced a vitamin E consumption of up to 100% in the stratum corneum and viable epidermis, and a vitamin C consumption of only 21% in the stratum corneum. Simultaneously applied vitamin E and vitamin C also completely protected against UVB-radiation-induced lipid peroxidation (P < 0.05), and lower antioxidant doses were needed compared to vitamin E or vitamin C alone. In the presence of vitamin C, epidermal vitamin E was more stable upon UVB irradiation (P < 0.05), suggesting interaction between vitamin E and vitamin C. In conclusion, topically applied vitamin E and/or vitamin C efficiently protect against UVB-radiation-induced lipid peroxidation in the presence of eicosapentaenoic acid. The beneficial biological effects of eicosapentaenoic acid may therefore be improved if vitamin E and/or vitamin C are present in sufficient amounts. The ex vivo pig skin model provides a useful tool for assessing short-term biochemical effects related to UVB radiation, without the use of living experimental animals.     

Different populations of pig epidermal cells: isolation and lipid composition.

Preparations representing populations of (a) basal and spinous cells, (b) granular cells, and (c) stratum corneum cells were obtained by successive treatments of epidermal slices from pig skin with dilute buffered trypsin solutions. Total lipids accounted for about 8% of the cell dry weight in each of the three populations. Phospholipids, which predominated in the basal and spinous cells, accounted for only 21% of the total lipids in the granular cells and less than 0.1% in the stratum corneum. The latter cells contained more cholesterol (23% of total lipid) than either the granular cells (18%) or the basal and spinous cells (8%). The proportion of ceramide was also much higher in the stratum corneum (17%) and granular cells (9%) than in the basal and spinous cells (1%). The relative amounts of glycosphingolipid (glucosylceramide) and cholesteryl sulfate in the total lipids of stratum corneum cells were less than half those in the granular cells and basal and spinous cells. A novel phospholipid was a major component (26% of total) of the phospholipids from granular cells. The compound, which was partially characterized, contained phosphorus, fatty acids, and glycerol (molar ratio 1:3:2) and appeared to be a neutral derivative of phosphatidic acid.     

Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL-1β

There is a tight interaction of the bone and the immune system. However, little is known about the relevance of the complement system, an important part of innate immunity and a crucial trigger for inflammation. The aim of this study was, therefore, to investigate the presence and function of complement in bone cells including osteoblasts, mesenchymal stem cells (MSC), and osteoclasts. qRT-PCR and immunostaining revealed that the central complement receptors C3aR and C5aR, complement C3 and C5, and membrane-bound regulatory proteins CD46, CD55, and CD59 were expressed in human MSC, osteoblasts, and osteoclasts. Furthermore, osteoblasts and particularly osteoclasts were able to activate complement by cleaving C5 to its active form C5a as measured by ELISA. Both C3a and C5a alone were unable to trigger the release of inflammatory cytokines interleukin (IL)-6 and IL-8 from osteoblasts. However, co-stimulation with the pro-inflammatory cytokine IL-1β significantly induced IL-6 and IL-8 expression as well as the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) indicating that complement may modulate the inflammatory response of osteoblastic cells in a pro-inflammatory environment as well as osteoblast-osteoclast interaction. While C3a and C5a did not affect osteogenic differentiation, osteoclastogenesis was significantly induced even in the absence of RANKL and macrophage-colony stimulating factor (M-CSF) suggesting that complement could directly regulate osteoclast formation. It can therefore be proposed that complement may enhance the inflammatory response of osteoblasts and increase osteoclast formation, particularly in a pro-inflammatory environment, for example, during bone healing or in inflammatory bone disorders.     

Lipid lymphocyte chemoattractants in psoriasis

In view of the evidence that lymphocyte infiltrates are a constant feature of the skin lesions of psoriasis and the demonstration that certain hydroxylated metabolites of arachidonic acid are present in lesional psoriatic skin and possess lymphocyte chemoattractant properties, lipid extracts of samples from lesional and normal skin were assayed to determine which are the predominant lipid lymphocyte chemoattractants in psoriasis. Dilution-related lymphocyte chemoattractant activity was found in lipid extracts of stratum corneum samples from psoriatic lesions, but not in similar extracts the samples from both sources contained equivalent amounts of this activity. Subsequent purification of lesional stratum corneum lipid extracts by straight and reversed phase high performance liquid chromatography (HPLC) revealed the presence of at least two different lipid chemoattractants, one major component being identified as 12-(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12[R]-HETE) by its biological and chromatographic properties. These compounds may play a role in the pathogenesis of the lymphocyte infiltrates in psoriatic lesions.     

Mesenchymal stroma/stem‐like cells of GARP knockdown inhibits cell proliferation and invasion of mouse colon cancer cells (MC38) through exosomes

Mesenchymal stroma/stem‐like cells (MSCs) have antitumour activity, and MSC‐derived exosomes play a role in the growth, metastasis and invasion of tumour cells. Additionally, glycoprotein A repetition predominant (GARP) promotes oncogenesis in breast cancer. Therefore, GARP is speculated to be a target gene for cancer therapy. We aimed to explore the therapy role of MSC‐derived exosomes targeting GARP in mouse colon cancer cell MC38. We successfully established a GARP knockdown system using three kinds of siRNA‐GARP in MSC cells. Exosomes were isolated from MSC and siGARP‐MSC cells, and verified by the exosome surface protein markers CD9, CD63 and CD81. GARP expression was significantly decreased in siGARP‐MSC exosomes compared with that of MSC exosomes. We found that siGARP‐MSC exosomes inhibited cell proliferation, migration and invasion of MC38 cells, using CCK‐8, colony formation, wound‐healing and Transwell invasion assays. Furthermore, siGARP‐MSC exosomes impeded IL‐6 secretion and partly inactivated JAK1/STAT3 pathway, measured using ELISA and RT‐qPCR. In conclusion, MSC‐derived exosomes targeting GARP are a potential strategy for cancer therapy.     

Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis

Background

Although recent studies indicate a crucial role for IL-17A and IL-22 producing T cells in the pathogenesis of psoriasis, limited information is available on their frequency and heterogeneity and their distribution in skin in situ.

Methodology/Principal Findings

By spectral imaging analysis of double-stained skin sections we demonstrated that IL-17 was mainly expressed by mast cells and neutrophils and IL-22 by macrophages and dendritic cells. Only an occasional IL-17^pos, but no IL-22^pos T cell could be detected in psoriatic skin, whereas neither of these cytokines was expressed by T cells in normal skin. However, examination of in vitro-activated T cells by flow cytometry revealed that substantial percentages of skin-derived CD4 and CD8 T cells were able to produce IL-17A alone or together with IL-22 (i.e. Th17 and Tc17, respectively) or to produce IL-22 in absence of IL-17A and IFN-γ (i.e. Th22 and Tc22, respectively). Remarkably, a significant proportional rise in Tc17 and Tc22 cells, but not in Th17 and Th22 cells, was found in T cells isolated from psoriatic versus normal skin. Interestingly, we found IL-22 single-producers in many skin-derived IL-17A^pos CD4 and CD8 T cell clones, suggesting that in vivo IL-22 single-producers may arise from IL-17A^pos T cells as well.

Conclusions/Significance

The increased presence of Tc17 and Tc22 cells in lesional psoriatic skin suggests that these types of CD8 T cells play a significant role in the pathogenesis of psoriasis. As part of the skin-derived IL-17A^pos CD4 and CD8 T clones developed into IL-22 single-producers, this demonstrates plasticity in their cytokine production profile and suggests a developmental relationship between Th17 and Th22 cells and between Tc17 and Tc22 cells.     

Stratum corneum lipid phase transitions and water barrier properties

In mammals, the outer skin layer, the stratum corneum, is the ultimate barrier to water loss. In order to relate barrier function to stratum corneum structure, samples from porcine skin were investigated by using differential scanning calorimetry (DSC), infrared (IR) spectroscopy, and water permeability techniques. Results of DSC and IR studies show that stratum corneum lipids undergo thermal transitions between 60 and 80 degrees C similar to lipid thermotropic transitions seen in a variety of synthetic and biological membranes. Results of water flux experiments performed under conditions similar to those of the DSC and IR studies show an abrupt change in permeability at about 70 degrees C. At low temperatures, water flux values are similar to those obtained for human skin in vivo, yielding an activation energy of 17 kcal/mol, in excellent agreement with values obtained for water flux through a variety of lipid biomembranes. In contrast, at temperatures above about 70 degrees C, water flux is characterized by an activation energy only slightly higher than that of free diffusion, suggesting that the stratum corneum offers little diffusional resistance under these conditions. These combined results suggest that increased disorder in stratum corneum lipid structure, brought about by thermotropic transitions, results in dramatically altered diffusional resistance of this tissue to water flux. Thus, as found for numerous biological membranes, water flux and lipid order in porcine stratum corneum are inversely related.     

Lysis and phenotypic modulation of mesenchymal stromal cells upon blood contact triggers anti-inflammatory skewing of the peripheral innate immune repertoire

Background aimsMesenchymal stromal cells (MSCs) are used to treat immune-related disorders, including graft-versus-host disease. Upon intravenous infusion, MSCs trigger the instant blood-mediated inflammatory response, resulting in activation of both complement and coagulation cascades, and are rapidly cleared from circulation. Despite no/minimal engraftment, long-term immunoregulatory properties are evident. The aim of this study was to establish the effects of blood exposure on MSC viability and immunomodulatory functions.MethodsHuman, bone marrow derived MSCs were exposed to human plasma +/– heat inactivation or whole blood. MSC number, viability and cellular damage was assessed using the JC-1 mitochondrial depolarization assay and annexin V staining. C3c binding and expression of the inhibitory receptors CD46, CD55 and CD59 and complement receptors C3aR and C5aR were evaluated by flow cytometry. MSCs pre-exposed to plasma were cultured with peripheral blood mononuclear cells (PBMCs) and monocyte subsets characterized by flow cytometry. The PBMC and MSC secretome was assessed using enzyme-linked immunosorbent assays against tumor necrosis factor alpha, interleukin (IL)-6 and IL-10. Monocyte recruitment towards the MSC secretome was evaluated using Boyden chambers and screened for chemotactic factors including monocyte chemoattractant protein (MCP)-1. MSC effects on the peripheral immune repertoire was also evaluated in whole blood by flow cytometry.ResultsPlasma induced rapid lysis of 57% of MSCs, which reduced to 1% lysis with heat inactivation plasma. Of those cells that were not lysed, C3c could be seen bound to the surface of the cells, with a significant swelling of the MSCs and induction of cell death. The MSC secretome reduced monocyte recruitment, in part due to a reduction in MCP-1, and downregulated PBMC tumor necrosis factor alpha secretion while increasing IL-6 levels in the co-culture supernatant. A significant decrease in CD14⁺ monocytes was evident after MSC addition to whole blood alongside a significant increase in IL-6 levels, with those remaining monocytes demonstrating an increase in classical and decrease in non-classical subsets. This was accompanied by a significant increase in both mononuclear and polymorphonuclear myeloid-derived suppressor cells.ConclusionsThis study demonstrates that a significant number of MSCs are rapidly lysed upon contact with blood, with those surviving demonstrating a shift in their phenotype, including a reduction in the secretion of monocyte recruitment factors and an enhanced ability to skew the phenotype of monocytes. Shifts in the innate immune repertoire, towards an immunosuppressive profile, were also evident within whole blood after MSC addition. These findings suggest that exposure to blood components can promote peripheral immunomodulation via multiple mechanisms that persists within the system long after the infused MSCs have been cleared.     

Inhibition of Keratinocyte Differentiation by the Synergistic Effect of IL-17A,IL-22, IL-1α, TNFα and Oncostatin M

Keratinocyte differentiation program leading to an organized epidermis plays a key role in maintaining the first line of defense of the skin. Epidermal integrity is regulated by a tight communication between keratinocytes and leucocytes, particularly under cytokine control. Imbalance of the cytokine network leads to inflammatory diseases such as psoriasis. Our attempt to model skin inflammation showed that the combination of IL-17A, IL-22, IL-1α, OSM and TNFα (Mix M5) synergistically increases chemokine and antimicrobial-peptide expression, recapitulating some features of psoriasis. Other characteristics of psoriasis are acanthosis and down-regulation of keratinocyte differentiation markers. Our aim was to characterize the specific roles of these cytokines on keratinocyte differentiation, and to compare with psoriatic lesion features. All cytokines decrease keratinocyte differentiation markers, but IL-22 and OSM were the most powerful, and the M5 strongly synergized the effects. In addition, IL-22 and OSM induced epidermal hyperplasia in vitro and M5 induced epidermal thickening and decreased differentiation marker expression in a mouse model, as observed in human psoriatic skin lesions. This study highlights the precise role of cytokines in the skin inflammatory response. IL-22 and OSM more specifically drive epidermal hyperplasia and differentiation loss while IL-1α, IL-17A and TNFα were more involved in the activation of innate immunity.     

Expression of genes for metalloproteinases (MMP-1, MMP-2, MMP-9, and MMP-12) associated with psoriasis

Using real-time polymerase chain reaction (RT-PCR), we measured mRNA amounts of matrix metalloproteinases (MMPs): MMP-1, MMP-2, MMP-9, and MMP-12 genes in psoriatic lesions and unaffected skin of the same patients. We observed significant (about 15-fold) increase in the expression level of matrix metalloproteinase MMP-1 and MMP-12 genes associated with psoriasis. The results of our studies of MMP gene expression in cultured primary human keratinocytes treated with interleukin (IL-17) have shown upregulation of MMP gene expression both in cultured keratinocytes and in psoriatic skin lesions. Therefore, upregulation of MMP genes in the skin affected by psoriasis could result from IL-17 effects on skin cells.     

Comparative effects of cytokines and cytokine combinations on complement component C3 secretion by HepG2 cells

The mechanisms that control complement protein synthesis are incompletely understood. Recent evidence suggests that cytokines are involved in the regulation of hepatic synthesis of circulating complement components. Therefore, we compared the effects of human recombinant IL-1alpha, IL-1beta, IL-6, IFN-gamma, and TNF-alpha individually or in combination, on HepG2 secretion of complement component C3, the major opsonic protein of the complement system. HepG2 cells were incubated with each cytokine alone and with various combinations of the cytokines. At 24, 48, 72, and 96 h of incubation, the C3 and albumin secreted by the HepG2 cells were quantified by a sandwich ELISA. IL-1alpha and IFN-gamma significantly enhanced C3 secretion by the cells (P<0.02 vs. control cells). IL-1beta when combined with either IL-6 or IFN-gamma also increased C3 secretion (P<0.03 vs. control cells). The stimulatory effect on HepG2 cells by the IL-1beta/IL-6 combination was synergistic. With the exception of IL-1alpha, which increased albumin secretion, HepG2 secretion of albumin was not affected by incubation with individual cytokines or the cytokine combinations. Therefore, IL-1alpha, IFN-gamma, and the combination of IL-1beta with IL-6 or IFN-gamma specifically enhanced C3 secretion by HepG2 cells. The greatest magnitude of C3 secretion was induced by the combination of IL-1beta and IL-6.     

Temperature-Dependent Electrical and Ultrastructural Characterizations of Porcine Skin upon Electroporation

The mechanism of high-voltage pulse-induced permeabilization of the stratum corneum, the outer layer of the skin, is still not completely understood. It has been suggested that joule heating resulting from the applied pulse may play a major role in disrupting the stratum corneum. In this study, electrical and ultrastructural measurements were conducted to examine the temperature dependence of the pulse-induced permeabilization of the stratum corneum. The stratum corneum resistance was measured using a vertical diffusion holder, with the stratum corneum placed between two electrode-containing chambers. The stratum corneum resistance was reduced manyfold during the applied pulse. The extent of resistance reduction increased with pulse voltage until reaching a threshold value, above which the resistance reduction was less dependent on the pulse voltage. The stratum corneum was more susceptible to permeabilization at high temperature, the threshold voltage being lower. The stratum corneum resistance recovered within milliseconds after a single 0.3-ms pulse. High-temperature samples had a more prolonged recovery time. Using time-resolved freeze fracture electron microscopy, aggregates of lipid vesicles were observed in all samples pulsed above the threshold voltage. The sizes and fractional areas occupied by aggregates of lipid vesicles at 4°C and at 25°C were measured at different time points after the applied pulse. Aggregates of vesicles persisted long after the electric resistance was recovered. After pulsing at the same voltage of 80 V, samples at 4°C were found to have slightly more extensive aggregate formation initially, but recovered more rapidly than those at 25°C. The more rapid recovery of the 4°C samples was likely due to a lower supra-threshold voltage. Viscoelastic instability propagation created by the pulse may also play a role in the recovery of the aggregates.     

Noninvasive characterization of human stratum corneum of undiseased skin of patients with atopic dermatitis and psoriasis as studied by Fourier transform Raman spectroscopy

Etiopathogenetic regulatory disorders of epidermal metabolism and the subsequent changes in the molecular pattern of the stratum corneum play an important role in the clinical differentiation of particular dermatoses (e.g., psoriasis, atopic dermatitis). In this study we present in vitro Fourier transform Raman spectra of the stratum corneum from healthy skin, as well as from clinically undiseased skin of the right heel of atopic and psoriatic volunteers. Differences in the averaged spectra were detected, particularly in the spectral ranges of 1112-1142 (lipid band), 1185-1220, and 1394-1429 cm(-1). By using the first derivative of the averaged spectra and/or a statistical evaluation of the spectroscopic data it was possible to distinguish the skin types examined.     

Complement Regulatory Molecules on Human Myelin and Glial Cells: Differential Expression Affects the Deposition of Activated Complement Proteins

Abstract: The expression of decay-accelerating factor CD55, membrane cofactor protein CD46, and CD59 was studied on Schwann cells cultured from human sural nerve and myelin membranes prepared from human cauda equina and spinal cord. These proteins are regulatory membrane molecules of the complement system. CD55 and CD46 are inhibitors of C3 and C5 convertases and CD59 inhibits C8 and C9 incorporation into C5b-9 complex and C9-C9 polymerization. The presence of these proteins was assessed by using antibodies to each of the proteins by fluorescent microscopy, fluorescence-activated cell sorter analysis, and also sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot analysis. Schwann cells in culture expressed CD55, CD46, and CD59. It is interesting that only CD59 was detected on myelin from both central and peripheral nerve tissue. The ability of these proteins to limit C3 peptide deposition and C9 polymerization in myelin was studied by western blot analysis. C3b deposition was readily detected on antibody-sensitized myelin incubated with normal human serum used as a source of complement but not with EDTA-treated or heat-inactivated serum. C3b deposition was not affected by anti-CD55 antibody. On the other hand, poly-C9 formation in myelin, which was maximum when 50% normal human serum was used, was increased four- to fivefold when myelin was preincubated with anti-CD59. Our data suggest that complement activation on myelin is down-regulated at the step of the assembly of terminal complement complexes, including C5b-9, due to the presence of CD59.     

Cytokine network in psoriasis revisited

Psoriasis is a chronic genetically determined, erythemato-squamous disease associated with many comorbidities. Evidence from clinical studies and experimental models support the concept that psoriasis is a T?cell-mediated inflammatory skin disease and T?helper (Th) cells -?Th1, Th17 and Th22?- play an important role in the pathogenesis. Th1 cytokines IFNγ, IL-2, as well as Th17 cytokines IL-17A, IL-17F, IL-22, IL-26, and TNFα (Th1 and Th17 cytokine) are increased in serum and lesional skin. IL-22 produced by Th17 and new subset of T helper cells, Th22, is also increased within psoriatic lesions and in the serum. Other recently recognized cytokines of significant importance in psoriasis are IL-23, IL-20 and IL-15. The IL-23/Th17 pathway plays a dominant role in psoriasis pathogenesis. Currently due to enormous methodological progress, more and more clinical and histopathological psoriatic features could be explained by particular cytokine imbalance, which still is one of the most fascinating dermatological research fields stimulating new and new generations of researchers.