The role of inflammatory cell death in type 1 dominant inflammatory skin diseases

Summary

While there has been significant progress in the development of new therapies for psoriasis and atopic dermatitis in recent years, innovation in the field of type 1 dominant skin diseases is still limited. This category comprises diseases characterized by a cytotoxic immune reaction directed against resident skin cells. The histological correlate is interface dermatitis, defined by a subepidermal inflammatory infiltrate associated with epidermal keratinocyte apoptosis. Representative conditions include lichen planus, cutaneous lupus erythematosus, erythema multiforme, alopecia areata, and vitiligo. Immunologically, there is a dominance of Th1 cells, which mediate their effects through interferon‐γ and tumor necrosis factor‐α. Recent findings have shown that, in addition to apoptosis, other forms of cell death are also activated by this immune response, such as necroptosis. In contrast to apoptosis, necroptosis represents a strong immunological stimulus and thus further intensifies the local inflammatory response. These findings open new therapeutic perspectives, as numerous necroptosis inhibitors are currently under investigation for various inflammatory diseases. The present review summarizes the immunopathogenesis of type 1‐dominant skin diseases and highlights emerging therapeutic strategies, including the inhibition of inflammatory cell death.

THE CLINICAL PROBLEM

Inflammatory skin diseases affect up to 20% of the population in Western countries. While great progress has been made in recent years in the treatment of psoriasis, atopic dermatitis, and hidradenitis suppurativa, ¹ , ² the development of new therapeutic approaches for type 1 dominant inflammatory skin diseases remains limited. This category comprises disorders characterized by a cytotoxic immune reaction directed against resident skin cells. Histologically, the corresponding pattern is interface dermatitis, defined by the coexistence of a subepidermal inflammatory infiltrate – composed predominantly of lymphocytes – and epidermal cell death. ³ Immunologically, this inflammatory reaction is mediated by T helper cells 1 (Th1 cells) and cytotoxic T cells, ⁴ which led to the designation type 1 dominant inflammatory skin diseases. ⁵ Although each disease has a distinct immunopathogenesis, this definition groups together disorders that either show interface dermatitis histologically or involve immune‐mediated attack on other resident skin cells, resulting in cell death. ⁶ As a result, vitiligo, in which a cytotoxic immune response is directed against melanocytes, and alopecia areata, in which the hair follicle is the target organ of the immune response, are also classified as type 1 dominant inflammatory skin diseases. Other diseases in this group are listed in Figure 1. Physiologically, type 1 immunity serves to eliminate viruses and remove degenerated cells. Accordingly, it represents a response to intracellular processes in which pathogens cannot be eliminated by phagocytosis or neutralized by antibodies. ⁷ The key cytokines interferon (IFN)‐γ and tumor necrosis factor (TNF)‐α stimulate the activity of cytotoxic cells and also directly mediate cell death via various receptors. Current treatment options for type 1 dominant skin diseases are largely limited to corticosteroids, retinoids, UV therapy, and broad‐spectrum immunosuppressants. There is therefore a great need to better understand the pathomechanisms of this group of diseases in order to define new therapeutic approaches.

FIGURE 1.

Overview of diseases classified as type 1‐dominant inflammatory skin diseases.

HYPOTHESIS

Our primary hypothesis is that epidermal cell death contributes to the inflammatory response in type 1 dominant skin diseases and thus represents a potentially new therapeutic target. Our research therefore aims to gain a more detailed understanding of the mechanisms of epidermal cell death and to investigate specific inhibitors for their potential anti‐inflammatory effects in this group of diseases.

RESEARCH FOR PRACTICAL APPLICATION

Overview of the forms of cell death

There are various mechanisms that cause a body cell to die (Table 1). The unregulated form is necrosis, in which a cell cannot maintain its physiological function due to undersupply or physical influences (trauma, chemical burns, scalding, etc.). In contrast, apoptosis, necroptosis, ferroptosis, and pyroptosis proceed in specific steps that are reversible up to a certain point. Apoptosis contributes to the physiological regeneration of cells, tissues, and organs and does not trigger any further inflammatory response. It can be triggered both intrinsically and extrinsically and is controlled by caspases. Extracellularly, binding to death receptors can trigger apoptosis. Intrinsically, regulation occurs via the release of cytochrome C from the mitochondria. Both pathways result in DNA degradation and the breakdown of the cell into smaller vesicles, which are then degraded by phagocytic cells. However, since various viruses have exploited this to specifically inhibit apoptosis and thus gain a reproductive advantage, ⁷ further mechanisms of cell death that are independent of apoptosis are required. Necroptosis is regulated by a complex of RIPK1 and RIPK3, which together form the so‐called necrosome. This activates MLKL, which assembles with other molecules and forms pores in the outer cell membrane. This leads to an uncontrolled influx of fluid into the cell, causing the cell to swell and burst. The released cell organelles and DNA represent an attractive stimulus for immune cells, as they bind to pattern recognition receptors and thus drive an inflammatory response. ⁸ Another inflammatory cell death is pyroptosis. It is triggered by activation of the inflammasome and also leads to the formation of pores in the outer cell membrane, which are formed by proteins of the gasdermin family. As in necroptosis, the cell swells and bursts. In addition, Interleukin (IL)‐1β and IL‐18 are released, which induce a strong inflammatory response. ⁹ Finally, there is ferroptosis, in which free oxygen radicals cause lipid oxidation and membrane damage to the cell. Ferroptosis is named after the accumulation of iron in the cell, which promotes the generation of free oxygen radicals. ¹⁰ There are also reports in the literature of the simultaneous activation of several forms of cell death, known as PANoptosis. ¹¹ This has been described in particular in connection with severe viral infections, such as SARS‐COV2 pneumonia. ¹² Interestingly, specific inhibitors of inflammatory cell death have also been tested in this population. For example, a phase 1b study of the RIPK1 inhibitor eclitasertib in patients with severe COVID‐19 showed a tendency toward faster improvement in inflammatory biomarkers and clinical symptoms in the verum group compared to placebo, with overall good tolerability. ¹³ Other molecules that bind to or inhibit RIPK1, RIPK3, or MLKL are currently in development for inflammatory bowel disease, rheumatic diseases, Alzheimer's disease, amyotrophic lateral sclerosis, and other indications. ¹⁴

TABLE 1.

Overview of the most important characteristics of different forms of cell death.

	Necrosis	Apoptosis	Necroptosis	Pyroptosis	Ferroptosis
Activation	Insufficient oxygen/nutrient supply Physical hazards	Extrinsic: Death receptors (e.g., FAS ligand) Intrinsic: Cytochrome C release from mitochondria	Tumor‐Necrosis‐Factor‐α, Interferon‐γ, Toll‐Like‐Receptors, Stress signals	Toll‐Like‐Receptors, NOD‐Like‐Receptors, Inflammasome	Iron oxidation, free oxygen radicals
Mediators	–	Initiator caspases: 8, 9 Effector caspases: 3, 6, 7	ZBP1, TRIF, RIPK1, RIPK3, MLKL	Caspase 1	Protein kinase A, GPX4
Mechanism	Uncontrolled cell death	Cell fragmentation	Cell membrane pores, cell rupture	Cell membrane pores, cell rupture	Cell membrane damage through lipid peroxidation

Inflammatory cell death contributes to the inflammatory response in type 1 dominant inflammatory skin diseases

Type 1 dominant skin diseases are characterized by a cytotoxic immune response that presents histologically as interface dermatitis. To investigate the mechanisms that control interface dermatitis in more detail, we analyzed skin biopsies from patients with lichen planus and cutaneous lupus erythematosus using transcriptome analysis. This revealed a strong interferon‐mediated immune response and activation of apoptosis‐ and necroptosis‐mediating genes. Further experiments showed that inhibition of RIPK3, a key protein in necroptosis, leads to a significant reduction in keratinocyte cell death when stimulated with IFN‐γ and TNF‐α. ¹⁵ Consistent with our findings, another research group reported strong expression of ZBP1, a key regulator of RIPK3‐dependent necroptosis, in graft‐versus‐host disease. ZBP1 is induced by IFN‐γ in human keratinocytes and mediates the induction of necroptosis independently of RIPK1. ¹⁶ On the other hand, there are also cell‐specific mechanisms that protect keratinocytes from inflammatory cell death, such as death‐associated protein kinase 1 (DAPK1). We have observed that DAPK1 is strongly expressed in lichen planus and correlates with the severity of the interface reaction. However, knocking out DAPK1 in keratinocytes led to an increase in necroptosis and the release of pro‐inflammatory cytokines, suggesting that DAPK1 counteracts inflammatory cell death and inflammation in lichen planus. ¹⁷

Ongoing studies by our research group are investigating the role of other cell death mechanisms, such as ferroptosis and pyroptosis. Based on these studies, there are two therapeutic options for controlling inflammation in type 1 dominant skin diseases. One is by blocking the IFN‐γ signal and the other is by blocking inflammatory cell death. The former has already been described several times, as the use of Janus kinase inhibitors (JAKi) makes it possible to prevent the intracellular transmission of the IFN‐γ signal. Numerous case reports describe the positive effects of JAK inhibition, e.g., in lichen planus or cutaneous lupus erythematosus. ¹⁸ The approval of JAKi for the treatment of alopecia areata and vitiligo highlights the considerable potential of this therapeutic approach. ¹⁹ , ²⁰ We recently demonstrated that inhibition of Janus kinase TYK2 is a promising approach in cutaneous lupus erythematosus, as it achieved strong anti‐inflammatory effects in vitro, in ex vivo cultured skin biopsies and in a case series of patients with various subtypes of cutaneous lupus erythematosus. ²¹ Several clinical studies are currently underway to investigate the use of JAKi in lichen planus or cutaneous lupus erythematosus. In contrast, there are no clinical reports to date on the use of necroptosis inhibitors in inflammatory skin diseases. This is mainly due to the fact that there are currently no approved preparations available for off‐label use. In this respect, the concept of inhibiting inflammatory cell death for the treatment of type 1 dominant skin diseases is currently based on laboratory studies and mechanistic considerations. It has recently been shown that UVB‐mediated cell death of keratinocytes can be successfully prevented in vitro by the RIPK3 inhibitor GSK'872. ²² The advantage of pharmacological inhibition of necroptosis in humans is that, unlike JAK inhibition, this approach would not exert broad immunosuppressive effects, as inflammatory cell death occurs primarily at sites of inflammation. However, potential disadvantages include uncertain tolerability, particularly with regard to viral infections and malignancies, as inhibition of necroptosis could interfere with its physiological role in host defense and tumor surveillance. Previous clinical data on the use of necroptosis inhibitors in other diseases have not revealed any negative safety signals; however, these studies were limited to phase 1 or phase 2 trials with small patient populations and short treatment durations. ¹⁴ Further clinical data is therefore needed to better assess the therapeutic potential of new molecules that block inflammatory cell death in type 1 dominant skin diseases.

CONCLUSIONS FOR PRACTICE

Our data demonstrate that, in addition to apoptosis, inflammatory cell death is activated in interface dermatitis. Because this process may further amplify the local inflammatory response, key kinases mediating necroptosis represent potential therapeutic targets. Although necroptosis inhibitors have not yet been evaluated in dermatological indications, data from other disease areas indicate that pharmacological inhibition of necroptosis is feasible and has shown an acceptable safety profile in the limited study populations investigated to date. Consequently, further studies – particularly clinical trials assessing the efficacy and safety of necroptosis inhibitors in dermatology – are warranted to address the substantial unmet need for therapeutic options beyond JAK inhibitors in this group of diseases.

FUNDING

The work was funded by the Advanced Clinician Scientist Program of the German Foundation for Dermatology (Deutsche Stiftung Dermatologie e.V.) in collaboration with the German Dermatological Society (Deutsche Dermatologische Gesellschaft e.V., DDG; [https://derma.de/stipendien‐forschungspreise]) and the Working Group for Dermatological Research (Arbeitsgemeinschaft Dermatologische Forschung e.V., ADF; [https://www.adf‐online.de]). The DDG's Advanced Clinician Scientist Program was kindly supported by Abbvie Germany, Almirall, Bristol Myers Squibb, Lilly, Novartis, Sanofi, and UCB Pharma.

CONFLICT OF INTEREST STATEMENT

F.L. has been an advisor to and/or received speaker honoraria from AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Johnson & Johnson, LEO Pharma, Lilly, Novartis, Roche, Sanofi, Regeneron, UCB, Union Therapeutics, Hexal, and Incyte.