Among the vast majority of various skin diseases, psoriasis which, although widely studied, still remains a mystery for scientists. Psoriasis occurs with an average frequency of about 3% and there are about 125 million people suffering from this dermatosis worldwide (Armstrong and Read, 2020). Despite numerous studies, its pathogenesis is still not fully elucidated. Surely, it is an interplay between genetic predisposition and the influence of external stimuli which lead to severe immune disturbances in the skin (Hugh and Weinberg, 2018). Nevertheless, nowadays, psoriasis is perceived as much more than just a dermatosis because it has been associated with many accompanying diseases, often resulting in serious health complications (Oliveira Mde et al., 2015). Among several subtypes of psoriasis, the most frequent is the plaque type. It presents with erythematous-infiltrative lesions with superficial scaling (Rendon and Schäkel, 2019). Being one of the most common dermatoses, psoriasis brought the attention of dermatologists, both in the molecular, and clinical fields.

Relatively recently a group of six proteins called gasdermins have been identified. They have been labeled A-F, whereas the first five are most similar to each other (Zou et al., 2021). The hallmark of gasdermins is the presence of two domains: N-terminal and C-terminal, which are bound by a linker region, the latter domain is able to inhibit the first one (Tsuchiya, 2021). This structure confers the ability to cause pores in plasma membranes in cells, after being cleaved by particular enzymes, causing their death which was called pyroptosis (Tsuchiya, 2021). There has been quite a number of studies on the role of gasdermins but still, they are not fully understood.

Gasdermin B (GSDMB) is a protein from this particular family. Its encoding gene is located on chromosome 17q21 (Zou et al., 2021). It can be cleaved by granzyme A, and as for the caspases influence–it remains inconclusive (Panganiban et al., 2018; Hou et al., 2021; Sarrio et al., 2023; Yin et al., 2023). First studies reported on the GSDMB cleavage by caspases 3, 6, and 7, later papers suggested that there are many more enzymes that could cleave GSDMB, whereas finally there were suspicions that the ability to induce pyroptosis by the cleaved GSDMB depends on its isoform (Sarrio et al., 2023). Indeed, GSDMB has several isoforms that may exert different influence (Oltra et al., 2023; Sarrio et al., 2023). GSDMB is different from other gasdermins because of its lipid binding profile, but also its unobvious engagement in pyroptosis (Wang et al., 2023). GSDMB is characterized by the lack of the ability of autoinhibition but being active in its full-length form or as N-terminal domain solely (Kuc-Ciepluch et al., 2021; Ivanov et al., 2023). Its biological role is not clear and its participation in pyroptosis is not fully elucidated, it may be isoform-dependent (Rana et al., 2022; Kong et al., 2023); its role in cell proliferation and migration has been reported (Rana et al., 2022). GSDMB expression has been observed in the epithelium of the respiratory and gastrointestinal tract, liver, kidneys, or lymphocytes (Zou et al., 2021). So far, GSDMB has been reported in several diseases, most documented in asthma, cancers, and inflammatory bowel diseases (Feng et al., 2018; Kuc-Ciepluch et al., 2021; Zou et al., 2021). In all of the mentioned disorders, tissue overexpression of GSDMB is observed, including in several cancers (e.g., breast, cervical, gastrointestinal tract) (Das et al., 2017; Zou et al., 2021; Rana et al., 2022). GSDMB engagement in infections has been studied as well, e.g., its direct bactericidal influence in Shigella invasion (Wang et al., 2023). There are also several links between these disorders and psoriasis. Research has shown that psoriatics have 1.70–2.53-fold increased odds of developing Crohn’s disease (CD) and about 1.75-fold increased odds of developing ulcerative colitis (UC) compared to controls (Fu et al., 2018). They have a common genetic background which involves chromosomal locus 6p21 and IL23R and IL12B genes (Fu et al., 2018), (the prominent involvement of Th17 lymphocytes), dysregulation of microbiota plays a role in both diseases as the reduction in the population of beneficial bacteria occurs (Cottone et al., 2019). Surprisingly, it has been reported that psoriasis is associated with another disease related to GSDMB–asthma (Östling et al., 2019). Apparently, both diseases have similar immune profile, focused on IL17, and patients suffering from asthma in whom high levels of IL17 are detected tend to have more frequent exacerbations, airway neutrophilia or less diverse lung microbiota (Östling et al., 2019). Additionally, there have been several genes discovered that differentially expressed in subjects with high IL17, were the same which are known to be altered in psoriasis (Östling et al., 2019). In this study, we decided to investigate the role of GSDMB in psoriasis. Based on several rationales, we believe it could play a role in its pathogenesis. GSDMB has been suggested to be involved in the proliferation and migration of cells and impaired keratinocytes proliferation and differentiation is a hallmark of psoriasis (Lanna et al., 2019; Rana et al., 2022), moreover GSDMB has been implicated in the pathogenesis of several disorders associated with psoriasis (Das et al., 2017; Cottone et al., 2019; Rana et al., 2022).

In our recent papers, we have proved that GSDMD and GSDME could be involved in the pathogenesis of psoriasis and also potentially become a novel marker of psoriasis (Nowowiejska et al., 2023a; Nowowiejska et al., 2023b). In the current study, we are presenting for the first time the results of combined serum, urine and tissue investigation of GSDMB.

The approval for the study was received from the Bioethics Committee of the Medical University of Bialystok (APK.002.303.2022 and APK.002.19.2020) and was conducted by the principles of the Declaration of Helsinki (WMA, 2022). A total of 60 patients (21 women, 39 men) with exacerbation of plaque psoriasis, with a mean age of 50 ± 2.34 years, and 30 gender- and age-matched volunteers without skin diseases and with a negative family history of psoriasis were included in the study on the gasdermin family. Informed consent was signed by all participants before inclusion in the study. Several exclusion criteria from the study were applied: age under 18 years, pregnancy and breastfeeding, other variants of psoriasis than plaque, dietary restrictions, taking oral medications at least 3 months before the study, autoimmune diseases other than psoriasis, renal impairment, and neoplasms. Psoriasis severity was evaluated using the Psoriasis Area and Severity Index (PASI) and was always performed by the same doctor. PASI score is based on the assessment of erythema, infiltration and scale associated with psoriatic skin lesions with regard to the body area involvement. The higher the score, the more severe psoriasis (Žurauskas et al., 2020). The PASI score was considered mild when PASI <10 (PASI I), moderate when PASI 10–20 (PASI II), and severe when PASI> 20 (PASI III). Moreover, basic laboratory tests were conducted before the study began. Serum, urine and tissue samples were obtained from the same cohort and in the manner previously described (Nowowiejska et al., 2023a; Nowowiejska et al., 2023b).

The summary of the basic information about the participants is presented in Table 1.

There was no statistically significant difference between patients and volunteers from the control group in terms of age, gender or BMI (p = 0.6135, p > 0.9999, p = 0.4137, respectively).

GSDMB is expressed only in humans and seems slightly different from the rest of gasdermins (Zou et al., 2021), hence it requires a separate discussion. To the best of our knowledge, serum and urinary GSDMB concentrations, as well as its expression in immunohistochemistry, have never been investigated in psoriatics before.

The role of GSDMB still remains uncertain however, there are studies on its function in different disorders. Impaired GSDMB function may lead to uncontrolled inflammatory responses (Yin et al., 2023). Considering the association between psoriasis, IBD, and asthma, as well as documented engagement of GSDMB in IBD and asthma pathology (Chao et al., 2017; Das et al., 2017; Rana et al., 2022), we found it interesting to study this gasdermin in psoriatics. There is evidence of GSDMB upregulation in intestinal epithelial cells (IECs), especially colonocytes/crypt top colonocytes in patients with CD and UC, compared to controls without IBD (Rana et al., 2022). However, it also seems that GSDMB exerts a function other than enabling pyroptosis. Apparently, it promotes the migration of epithelial cells via the regulation of their adhesion (Rana et al., 2022). Furthermore, it has been shown that cells that lack GSDMB are characterized by lower proliferation (Rana et al., 2022). Our study revealed significantly more prominent expression of GSDMB in psoriatic plaques compared to uninvolved skin and controls, as well as higher serum GSDMB concentration which could indicate GSDMB role in psoriasis pathogenesis. Our idea is that, potentially, elevated levels of GSDMB indicate its stimulating effect on cell proliferation, whereas hyperproliferation of keratinocytes is a hallmark of psoriasis (Rendon and Schäkel, 2019). The epidermal turnover time in psoriasis is estimated to be about 4 days, whereas normally it is 28 days (Lowes et al., 2014).

Another disorder in which GSDMB has been investigated is asthma. Both asthma and psoriasis are related to IL17 signaling, chronic inflammation, impaired epithelium and barrier function (Busse, 2019; Östling et al., 2019). In psoriasis, IL17 is responsible for the hyperproliferation of the epidermis which we clinically perceive as scaly lesions (Furue et al., 2020). In asthma, IL17 is suspected to stimulate epithelial cells and fibroblasts to release neutrophil chemoattractants and granulocyte–macrophage colony-stimulating factor, resulting in neutrophilic infiltration in the lungs. Moreover, IL17A promotes the proliferation, migration, and contraction of smooth muscle cells. Interestingly, at the same time, an opposite, protective role of IL17 has been suggested, probably associated with the maintenance of epithelial integrity (Habib et al., 2022). Single nucleotide polymorphisms in GSDMB have been found to be associated with higher GSDMB expression which translates into asthma severity and a higher number of disease exacerbations (Li et al., 2021). The suspected role of GSDMB in asthma is based on apoptosis of epithelial cells regulation, hence cell proliferation, differentiation, moreover upregulation of the expression of airway remodeling genes, chemokines, and heat-shock proteins (Zhao et al., 2015; Li et al., 2021). Hence, there is another piece of evidence of the GSDMB engagement in epithelial cell turnover that could be a potential contribution to psoriasis pathology.

To our knowledge, there are only two other papers about GSDMB in psoriatic skin to date. In the first one, GSDMB gene expression was studied in a small number of psoriatic plaque samples and the highest expression was observed in the stratum basale of the psoriatic epidermis compared to other layers and it was higher than in controls (Zhang et al., 2022). In the second study, the expression of GSDMB in psoriatic epidermis was decreased compared to healthy skin (Ji et al., 2023). The authors of the latter study stated that decreased GSDMB in psoriasis leads to inhibition of cell proliferation and stimulates apoptosis (Ji et al., 2023). Taking into account that the lack of GSDMB had been linked to decreased cell proliferation in the past (Rana et al., 2022), psoriasis is known for decreased apoptosis (Shou et al., 2021), and those authors observed downregulation of GSDMB, these results do not correspond to psoriasis pathogenesis. Additionally, the results we obtained are the opposite. A more suitable explanation would be that GSDMB affects cell adhesion and controls cell proliferation, and considering we found it overexpressed in psoriasis, it is convergent with the increased proliferation rate of psoriatic epidermis. Moreover, our hypothesis matches what is observed in psoriasis histologically, namely, a widening of the intercellular spaces and a decreased expression of adherens junction proteins which lead to changes in adhesion between cells (Shutova et al., 2023). In case of IBD, the lack of GSDMB resulted in IECs hyperadhesiveness due to inhibition of cell motility (Rana et al., 2022). The opposite situation, confirming these findings, was observed in the study on breast cancer by Hergueta-Redondo et al. (Hergueta-Redondo et al., 2014). They found that overexpression of GSDMB in breast cancer cells is associated with increased cell motility and invasiveness so exhibits prometastatic influence (Hergueta-Redondo et al., 2014).

There is also evidence that IFNγ stimulates GSDMB expression (Zhou et al., 2020). At the same time, IFNγ is elevated in psoriasis and correlates with the disease activity (Grän et al., 2020). That could be another link between psoriasis and GSDMB, however, unfortunately, in this study, we did not find a correlation between PASI and serum GSDMB, as well as there were no differences between GSDMB expression in the psoriatic plaque depending on PASI, so it cannot be considered skin lesions severity marker.

As for another cytokine, that could provide a link between psoriasis and GSDMB, it has been demonstrated in vitro that overexpression of GSDMB in human bronchial epithelium upregulates some genes, including TGF-β1 (Das et al., 2017). This cytokine is also involved in psoriasis and increased plasma TGF-β is found in psoriatic patients (Flisiak et al., 2003).

In this study, we decided to examine GSDMB also in the serum and urine of all participants because they are collected in a less invasive way than a tissue sample and could be potentially used in clinical practice. Considering serum GSDMB and urinary GSDMB/creatinine concentration ratio were significantly different between psoriatic patients and controls, they could be further evaluated as potential psoriasis markers; in case of serum–an increased GSDMB, and in case of urine–a decreased GSDMB/creatinine concentration ratio. Obviously, it requires further validation but the application of urine in daily clinical practice would be non-invasive and widely acceptable by the patients. To the best of our knowledge, there is no other study in which urinary GSDMB would be analyzed.

GSDMB serum concentration was significantly higher in male patients and correlated with age, so perhaps its influence is more evident in older individuals.

It has been shown that GSDMB can also interact with the other gasdermin, namely, GSDMD. GSDMB is able to activate caspase four which further leads to cleavage of GSDMD (Chen et al., 2019). In our earlier experiment, which has been published (Nowowiejska et al., 2023b), we also studied the role of GSDMD in psoriasis and found it overexpressed in psoriatic plaque compared to healthy skin and suggested its role in psoriasis which seems convergent with what we observed now.

In this study, we found significant expression of GSDMB in the dermis, especially in elastic fibers. However, we have not found any other information about GSDMB role within the dermis and in relation to these particular fibers. The role of elastin in psoriasis has not been specified either. Therefore, the prominent presence of GSDMB in this skin layer remains to be elucidated.

The limitation of our study was a relatively low number of participants, especially in the group who donated tissue samples however, because of the invasiveness of this procedure, people are not always willing to take part in such investigations. Hence our idea is to use less invasive biological material, namely, serum or urine. Another limitation is the detection limit of the ELISA kit. An important issue that must be taken into account is that there are several isoforms of GSDMB uncovered and they may exert different functions (Sarrio et al., 2023). In this study, we examined total GSDMB concentration. The lack of precise data on the GSDMB dynamics in normal health conditions with regard to demographic parameters also impedes the interpretation of the obtained results.

In the future, we would also like to study the influence of classic antipsoriatic agents and biological drugs on GSDMB in psoriasis. We would also like to distinguish between cleaved and not cleaved forms of GSDMB.

GSDMB supposedly plays a different role in psoriasis than other gasdermins because its primary function seems to be not pyroptosis but regulation of cell migration. Considering our findings, namely, overexpression in psoriatic plaque compared to healthy skin and increased serum concentration compared to subjects without psoriasis, it is clear that GSDMB might be involved in psoriasis pathogenesis. Elevated serum GSDMB and decreased urinary GSDMB/creatinine concentration ratio could be potential psoriasis markers, associated particularly with cell migration. GSDMB could be considered in the future as an interesting potential therapeutic target.