Inflammatory skin diseases, also called inflammatory dermatoses, are a group of immune-mediated skin diseases with a complex etiology in which both genetic and environmental (i.e., lifestyle) factors play an essential role [1]. Psoriasis and hidradenitis suppurativa (HS) are two of the many diseases that are encompassed by this term [1]. These two disorders, although clinically very diverse, share several pathogenetic pathways, including, in both cases, an unbalanced interaction between the adaptive and innate immune systems [2]. Psoriasis and HS also share potential environmental factors for the development and exacerbation of both diseases, which include smoking, alcohol intake, obesity, metabolic syndrome, and dysbiosis [3,4,5,6,7,8]. The molecular changes in the psoriatic skin lead to the activation and proliferation of keratinocytes, causing epidermal hyper- and parakeratosis, as well as neutrophilic infiltration of the epidermis [9]. Moreover, the critical element of HS pathogenesis includes the occlusion of the infundibulum of the pilosebaceous unit, its dilation, and rupture, followed by a creation of inflammatory nodules and tunnels with progressive scarring [7]. Interestingly, similarly to psoriasis, the occlusion of the pilosebaceous unit in HS is initiated by the hyperkeratosis and hyperplasia of the keratinocytes localized mainly in the infundibular epithelium [7,9]. The multitude of ongoing studies on the pathomechanisms of psoriasis and HS have led to its meticulous description. It is known that in both disorders, the activation of the dendritic cells, secretion of IL-23, and subsequent differentiation of T helper lymphocytes (Th) lead to the increased proliferation of Th17, Th1, and Th22 [7,10,11]. These T-cells cause the excessive production of interleukin (IL)-17, IL-22, and tumor necrosis factor-alpha (TNF-α) [7,10,11], which, as a result, drives the vicious inflammatory cycle leading to the further development of CD4+ T-cells and production of inflammatory cytokines [7,10,11]. Moreover, in the pathogenesis of HS, additional pathogenetic pathways have been described [7]. Complement activation by pathogen- and damage-associated molecular patterns (PAMPs and DAMPS) leads to inflammasome activation, the production of caspase-1, and release of IL-1β and TNF-α [12]. Although many pathogenetic pathways of both diseases have already been described, the exact pathomechanism is still yet to be fully elucidated. Pathogenetic advancements have led to the development of many pathway-specific medications, including biologics and Janus kinase inhibitors (JAKi) [6,12].

The similar pathomechanisms of the two disorders allow for the interchangeable use of psoriatic drugs in HS patients [2]. Nonetheless, even the newest biological drugs, allowing us to almost entirely eradicate skin lesions in psoriatic patients, frequently present incomparably worse responses in patients with HS [13,14]. Therefore, future research targeting possible inflammatory pathways in both diseases is necessary for the development of new, effective therapies. 

The removal of damaged and senescent cells is crucial for maintaining the homeostasis of every healthy multicellular organism. There are two basic pathways of programmed cell death, lytic and non-lytic [15]. Initially, only apoptosis was known to be programmed and strictly regulated, while necrosis was considered a form of unregulated cell death [15]. Recently, scientists have discovered differently regulated pathways of necrosis that may be activated by regulated stimuli [16]. Necroptosis and pyroptosis, classified as lytic forms of programmed cell death, were also considered inflammatory due to the release of proinflammatory molecules (DAMPs and cytokines) [16,17]. Both necroptosis and pyroptosis are examples of regulated necrosis; nonetheless, they are triggered by different stimuli and follow different pathways [15]. Pyroptosis, as a form of cell death, was first described in murine macrophage models by Zychlinsky et al. [18] in 1992. At first, it was incorrectly classified as apoptosis and later identified as a form of non-apoptotic cell death [15]. The word pyroptosis comes from Greek and translates into pyro (fire), ptosis (falling) [19]. The pyroptosis begins with the activation of inflammasomes, complex assemblies of multiple proteins activating caspase-1. Various distinct inflammasomes have been identified, each characterized by their unique activators, receptor classes, and the type of activated caspase [20]. The NLR family pyrin domain containing 3 (NLRP3) inflammasome should be underlined due to recent studies on its function in the development of inflammatory dermatoses [21,22,23].

Inflammasomes are innate immune system protein complexes that act as receptors or sensors to PAMPs and DAMP by promoting the maturation of proinflammatory IL-1β and IL-18 [24]. Inflammasomes form when cellular sensors detect PAMPs or DAMPs. The cellular sensors include, among others, absent in melanoma 2 (AIM2), caspase recruitment domain-containing protein 8 (CARD8), NOD-like receptors (NLRs), and pyrin. These sensors then trigger the activation of the effector enzyme through an adaptor molecule known as ASC (apoptosis-associated speck-like protein containing a CARD) [25]. During pyroptosis, caspase-1 cleaves gasdermin D (GSDMD), releasing its N-terminal domain from the C-terminal domain [26]. Additionally, caspase-11 and its human counterparts, caspase-4 and -5, can trigger pyroptosis by cleaving GSDMD at the same site as caspase-1 [26,27,28]. Once GSDMD is cleaved, the liberated N-terminal fragments undergo structural changes, leading to their oligomerization in the cellular membrane and the formation of large transmembrane β-barrel pores [29]. These β-barrel pores serve as channels connecting the cytosol to the extracellular space, allowing the release of DAMPs, including mature IL-1β, which attracts immune cells and triggers inflammation [28,30,31]. As previously mentioned, IL-1β has a crucial role in the differentiation and activation of Th17 cells producing IL-17 [32]. Moreover, IL-1β has been reported to be significantly increased in patients with psoriasis and even more in HS, both on the transcriptional and protein levels [33,34]. Furthermore, HS lesional and non-lesional adjacent skin shows a higher expression of IL-1β in comparison to healthy controls (HC) (data yet not published). While various mechanisms for the secretion of IL-1β from viable cells have been described in recent studies [35], pyroptosis and necroptosis are increasingly recognized as the primary pathways responsible for the release of IL-1β and IL-18, DAMPs, ATP, HMGB1, S100 proteins, and IL-1α [36]. Pyroptosis and apoptosis can be differentiated in several ways [15]. Morphologically, pyroptosis is characterized by a rapid loss of plasma membrane integrity through pore formation, as opposed to the membrane blebbing seen in apoptosis. The subcellular events leading to plasma membrane breakdown in pyroptosis occur within minutes, which is in stark contrast to the relatively slow process of apoptosis. The degradation of membrane structure in pyroptosis leads to the influx of water and ions, resulting in cell swelling and eventual rupture [37]. The non-canonical and canonical pathways are demonstrated in Figure 1.