Interleukin-1 Links Autoimmune And Autoinflammatory Pathophysiology in Mixed-Pattern Psoriasis Part 2

3.1. Autoimmune Processes in Psoriasis. Autoimmune

Autoimmune Processes in Psoriasis. Autoimmune signature in psoriasis seems driven by local and systemic Th17 patterns, expressing IL-17A, IL-22, and IFN-γ [10] (Figure 3). Chronic-stimulated dendritic cells sustain activation and differentiation of lesional Th17 cells primarily through secretion of IL-23 [15].

Both HLA restriction and T cell peptide specificity are determined by the T cell receptor repertoire. Antigenic stimulation triggers T cells’ activation and clonal expansion. In the absence of foreign antigens, clonal T-cell expansion likely suggests autoimmunity in inflammatory diseases [16].

Psoriasis seems to be driven by locally prevailing antigens [17]. Environmental factors are mostly rated, including stress, smoking, drugs, and infections [18]. Activated clonal T cells exert disease inflammatory process in combination with locally inflammatory leucocytes. In the last years, putative autoantigens like cathelicidin LL-37, melanocytic ADAMTSL5, lipid antigen PLA2G4D, and keratin 17 have been identified in psoriasis [19–22].

Psoriasis is an immune-mediated skin disease, which has a certain relationship with immunity.

1. Immune system overreaction

The immune system of patients with psoriasis may overreact, leading to abnormal secretion of cytokines and an imbalance of skin cell metabolism, resulting in the onset of the disease. This suggests that normal regulation of the immune system is essential for the health of psoriasis patients.

2. Decreased immune regulation function

The immunoregulatory function of patients with psoriasis generally decreases, including the decrease in the number and activity of immune cells such as overall T cells, CD4+T cells, CD8+T cells, and NK cells. This may be related to certain autoantibodies, immune complexes, and other factors in the patient's serum.

3. Associated with an inflammatory response

Psoriasis occurs on the surface of the skin, and the lesion often presents inflammatory reactions such as erythema, scales, and papules. Therefore, it is closely related to inflammation-related factors in the body (such as IL-6, TNF-α, IL-1β, etc.). The effects of the immune system may be closely related to the inflammatory response.

Generally speaking, immunity has an inseparable relationship with the occurrence and development of psoriasis. The key to the treatment of psoriasis is to regulate the function of the immune system, reduce the inflammatory response, and prevent the further spread of the disease. It can be seen that we need to significantly improve immunity to resist viruses. Cistanche can enhance immunity. Cistanche also has anti-virus and anti-cancer effects, which can strengthen the immune system’s ability to fight and improve the body’s immunity.

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3.2. Crosstalk between Adaptive and Innate Immunity in Psoriasis.

Complex crosstalk between the innate and adaptive immune systems in psoriasis adds up to antigen-specific exacerbation of inflammation in psoriasis. The accumulating circumstantial evidence suggests that in patients with stable and mild psoriasis, adaptive immunity is likely more prevalent, while innate immunity might contribute more to active and severe disease, systemic involvement, and comorbid conditions [23] (Figure 3). The coexistence of comorbidities like atherosclerosis in severe psoriasis has been interpreted as a systemic inflammatory reaction to the innate local inflammation in affected tissues [24]. The involved factors are not psoriasis-specific, though they magnify the overall inflammatory burden in patients with severe psoriasis.

The studies addressing the interplay between IL-17- and IL-36-driven inflammation might help understand how certain mediators influence the psoriasis spectrum by shifting innate or adaptive immunity [25]. All IL-36 isoforms (IL-36α, β, and γ) are members of the IL-1 family and are expressed in psoriatic skin [26]. They bind to a specific receptor (IL-1RL2), triggering the transcription of several inflammatory mediators through NF-κB activation.

The IL-36 seems to be associated with the clinical manifestation of specific psoriatic phenotypes. The skin in psoriasis vulgaris differs significantly from that in pustular psoriasis, representing opposite ends of the psoriasis spectrum. The balance between IL-36 and IL-17 might contribute to differential clinical symptoms between the vulgaris and pustulosa forms, in line with the response to given therapies [27].

The IL-23/IL-17 axis is key as it comprises innate immunity (IL-23-producing myeloid cells) and adaptive immunity (Th17- and IL-17-expressing CD8+ T cells). Understanding psoriasis might help shed light on such relationships.

3.3. On How IL-1 and IL-8 Participate in Th1 and Th17 Activation by IL-12/23.

Some cytokines, including IL-1, induce IL-17 release in human T lymphocytes. Their ability to promote Th17 cells depends not only on the induction of IL-23, IL-6, and TGF-β by dendritic cells but also on directly or indirectly activating the inflammasome and inducing IL-1β.

IL-12 and IL-23 are extremely important to induce Th1 and Th17, respectively, and their production mediated by antigen-presenting cells is distinctively regulated. Innate immunity-derived stimuli regulate IL-12 and IL-23 production, influencing the induced T lymphocyte phenotype. IL23 promotes IL-23R expression in myeloid cells and induces proinflammatory TNF-α and IL-1β cytokine production. Further, IL-23 promotes CD4+ precursors’ differentiation to the Th17 effector in the absence of IFN-γ and IL-4 [28].

IL-1 promotes lymphocytes’ growth and differentiation. The differential expression of IL1R1 in CD4 T lymphocyte subtypes confers different effector functions.

Th17 cells’ response to IL-12 and sustained exposure to IL-23 promote Th17 change to the Th1 phenotype [29], indicating the strong environmental influence [30]. Th17- derived Th1 cells are called “nonclassic Th1” and express CD161 and IL1R1 [31]. IL-1β and IL-23 combination promotes T cells’ production with the Th17 and Th1 phenotype in CD4+ CD161+ and CD4+ CD161- cell fractions. This suggests that Th1 cells respond to IL-1β and that CD4+ CD161+ clones in inflamed tissue can produce IFNgamma and express IL1R1 mRNA [32].

IL-8 (CXCL8) participates in the pathophysiology of psoriasis recruiting neutrophils and other inflammatory leukocytes. IL-8 highly expresses in plaque psoriasis and, up to tenfold, in pustular psoriasis [25].

IL-36, highly expressed in plaque psoriasis, acts on keratinocytes and myeloid dendritic cells [33] and is a potent inducer of the neutrophil CXCL1 and IL-8 chemotactic cytokines. Infiltrating neutrophils play a fundamental role in psoriatic plaque, amplifying the IL-36-mediated autoinflammatory loop in psoriasis [13].

4. Association of Inflammasomes with Innate and Adaptive Immunity

Inflammasomes are tripartite complexes comprising a cytoplasmic sensor, an adapter known as ASC, and procaspase1. Inflammasomes are defined by their cytoplasmic sensor, which includes AIM2, Pyrin, NLRP1, NLRP3, and NLRC4 and belong to the NOD2-like receptor family. Sensors’ diversity and specificity allow inflammasomes to respond to a wide range of either extrinsic (microbial molecules) or intrinsic (danger signals) stimuli.

The NLRP3 inflammasome is the prototypical and best-characterized inflammasome, and its activation has been sequenced [34]. A first signal, priming, provided by microbial molecules like lipopolysaccharide induces NLRP3 and pro-IL1β expression in an NF-κB-dependent fashion. Microbial molecules like toxins or danger signals like monosodium urate offer the second signal and trigger multimerization to make up an inflammasome (Figure 4).

The NLRP3 assembles to ASCs, leading to caspase-1 activation, which induces proteolytic maturation of IL-1β and IL-18 and Gasdermin D cleavage. The next pore formation of Gasdermin D in the cell membrane induces pyroptosis, a fast proinflammatory cell death [35]. Pyroptosis associated with the release of IL-1β, IL-18, and alarmins contributes to danger signal propagation beyond the damaged or infected cell, recruiting mono- and polymorphonuclear phagocytes (Figure 3). Oligomeric particles may be released from the inflammasome to further amplify the inflammatory response after phagocytosis by surrounding macrophages.

In intact phagocytes, IL-1β secretion can occur independently from pyroptosis. Autophagy regulates the inflammasome-processed cytokines, which induce IL-17. Autophagy intersects with the inflammasome-dependent generation of IL-1β and IL-18 at different stages. Autophagosomes can remove endogenous inflammasome-activating stimuli, including mitochondrial DNA, ROS, damaged lysosomes, pro-IL-1β, and inflammasome components as well. Autophagy inhibits IL-23 secretion due to its effects on IL-1β [36].

Figure 3: Schematic representation of inflammasome signaling mechanisms in mixed-pattern inflammatory diseases. Inflammatory agents and pathogens trigger the canonical inflammasome pathway. PAMPs and DAMPs are detected by specific innate immune sensors, leading to oligomerization and inflammasome assembly. The therapeutic targets in autoinflammatory diseases are as follows: signal 1 inflammasome activation: surface pattern recognition receptors like Toll-like receptors (TLR) and pathogen-associated molecular patterns stimulate the production of molecules like NF-κB and activate inflammasome assembly through downstream immunologic processes; signal 2 inflammasome activation: crystals in gout, heat-shock proteins, and damaged tissue as in burns, another pathogen- and damage-associated molecular pattern, activate inflammasome assembly through reactive oxygen species (ROS) production and downstream immunologic processes. Certain mediators influence the spectrum of psoriasis, shifting to innate or adaptive immune processes. 

The interplay between IL-17- and IL-36-driven inflammation seems involved in innate-adaptive immune balance. Inflammasome-induced hyperactive dendritic cells (DC) trigger enhanced T cell responses, preserving antigen and autoantigen presentation and contextualizing T helper cell responses through IL-1β, IL-18, and IL-23 secretion. These cytokines trigger Th1/Th17 responses. IL-18 amplifies IFN-γ production by Th1 cells and reinforces Th1 differentiation, while IL-1β promotes Th17 polarization and IL-17 secretion, causing a mixed autoinflammatory-autoimmune pathology. 

The image shows the potential sites for antibody-based therapeutic intervention (ABTI). ASC: apoptosis-associated speck protein; ER: endoplasmic reticulum; IFNAR: interferon-associated receptor; IFN: interferon; IL-1: interleukin1; IL-1 R: IL-1 receptor; IL-1Ra: IL-1 receptor antagonist; IL-6: interleukin 6; IL-6R: IL-6 receptor; IL-18: interleukin-18; JAK: Janus kinase; NLRP3: NOD-like receptor P3; ROS: reactive oxygen species; TLR: Toll-like receptor; TNF: tumor necrosis factor; TNF-R: TNF receptor; ASC: apoptosis-associated speck-like protein containing a CARD; CARD: caspase recruitment domain; DAMP: damage-associated molecular pattern; LPS: lipopolysaccharide; NLR: NOD-like receptor; NOD: nucleotide-binding oligomerization domain; PAMP: pathogen-associated molecular pattern; PYD: Pyrin domain; MMC: multimolecular complex; HMGB1: high-mobility group box 1; TCR: T cell receptor.

Involvement in a variety of pathophysiological conditions poses inflammasomes as interesting antibody-based therapeutic intervention targets (Figure 3). From a pathogenetic perspective, they are characterized by chronic activation of the immune system, causing tissue inflammation in genetically predisposed individuals. However, damage-specific effectors are different. In autoinflammatory diseases, the innate immune system directly causes tissue inflammation, while in autoimmune disorders, the innate immune system activates the adaptive immune system, ultimately responsible for the inflammatory process [37].

Some diseases have a mixed autoimmune-autoinflammatory root [38]. Inflammasome dysregulation is associated with autoinflammatory and autoimmune diseases like familial Mediterranean fever, rheumatoid arthritis, psoriasis, and systemic lupus erythematosus [4, 39]. Some immune-inflammatory diseases may reflect a variable expression in the pathogenetic autoinflammatory and autoimmune factors [40].

In an explanatory attempt, Polly Matzinger put forward the danger signal theory. This proposes that the immune system does not so much discriminate between endogenous and exogenous signals but increases responses to danger signals, regardless if they are exogenous pathogenic bacteria or endogenous damaged tissues [41]. However, the hazard model does not adequately explain the exquisite specificity of adaptive immune responses in autoimmune diseases. Recent advances in genetic and molecular studies allow converging to a united classification for all immunological diseases in a theoretical framework. Psoriasis, ankylosing spondylitis, Behcet’s syndrome, uveitis, and other diseases show a mixed pattern.

Inflammasome-hyperactivated dendritic cells elicit enhanced T-cell responses. They preserve their antigen-presenting function and contextualize T-helper cell responses through IL-1β and IL-18 secretion. These cytokines drive Th1/Th17 responses in particular. The IL-18 amplifies IFN-γ production by Th1 cells, while IL-1β promotes Th17 polarization and IL-17 secretion [42] (Figure 3).

Inflammasome-dependent IL-1β-driven Th17 responses are essential for host defense against infections by fungi like Candida albicans. The C-type lectins Dectin-1 are involved in host defense mechanisms against fungal infection, driving inflammatory and adaptive immune responses. Dectin-1 is a type-C lectin receptor that detects β-glucans [43]. This leads to Syk-dependent NF-κB activation and NLRP3 inflammasome assembly, while Th17 responses yield immune protection against the pathogen [44]. Notably, Dectin-1 signaling also triggers IL-1β production through a noncanonical caspase-8 inflammasome [45].

The divergent roles of IL-1β and IL-18 in adaptive immunity setup have drawn much attention to inflammasomes as adjuvants to vaccines. The Th1-mediated humoral responses, cytotoxic T cell/Th1/Th17 immunity, and immune memory can be manipulated using inflammasome-activating ligands [46]. Type I interferons inhibit pro-IL-1 synthesis, promote IL-18 maturation, and, combined with inflammasomes’ activation, might aid in modeling protective Th1 responses [47]. The vaccine adjuvant chitosan is a cationic polysaccharide that induces type I IFN production, NLRP3 inflammasome activation, and intense Th1 responses. More studies are needed to better understand the role of inflammasomes in pathological and protective immunity.

Apoptosis and pyroptosis are two well-studied cell death patterns, traditionally believed as unrelated. Emerging evidence shows their extensive interrelation as converging pathways, activating the same cell death effector, the pore-forming protein Gasdermin D [48].

Pyroptosis is the inflammatory cell death triggered by intracellular detection of signs of damage or pathogens [49]. Pyroptotic cells show swelling, fragmented genetic material, membrane pore formation, plasma membrane rupture, and release of inflammatory mediators and cytoplasmic content to the extracellular space [50]. Lipopolysaccharide, a hallmark of the gram-negative bacterial cell wall, is a prototypical trigger of immune cell pyroptosis. Pyroptosis starts with the innate TLR4 activation step. This induces NF-κB activation and translocation to the nucleus to boost gene transcription for precursors pro-IL-1β, pro-IL-18, and procaspases and intracellular Nod-like receptors’ transcription. In psoriatic lesions, Dectin-1 upregulation seems under the control of psoriasis-associated cytokines, while its role in the biology of skin inflammation and infection is to be explored [51].

The second signal induces the oligomerization of intracellular complexes called inflammasomes [52], which facilitate pro-IL-1β and procaspase-1 maturation into their active forms. While IL-1β is released and induces a proinflammatory state, caspase-1 breaks down the cytoplasmic gasdermin D, forming pores in the membrane and triggering cell death through cytoplasmic components’ leakage.

Autophagy is a self-degrading process required to restore cell homeostasis when menacing factors are detected [53]. This ubiquitous lysosomal degradation mechanism removes damaged proteins and organelles, contributes to antigen presentation to the cell surface, protects against genome instability, and prevents tissue damage. Autophagy is of physiological relevance, helping defend against damaging stress while leading to pathology when in excess or defect [54].

As an essential homeostatic mechanism, autophagy is upregulated in response to environmental and pharmacological triggers. It has a very important role in cancer, neurodegeneration, diabetes, and liver and autoimmune diseases. Molecular elements that lead to this type of cell death also collaborate in the stress response.

In the immune system, autophagy serves as a source of peptides for antigen presentation [55], provides a mechanism for the absorption and degradation of intracellular pathogens, and is a key regulator of inflammatory cytokines. It is also involved in regulating inflammasome activation and helping remove inflammasome components and endogenous activators [56] and plays a role in determining IL-1β fate in autophagosomes. Present understanding suggests that autophagy is a critical regulator of inflammasome activation and IL-1 family cytokines’ release [57].

5. Inflammasome-Induced IL-1 Promotes IL-17-Mediated Responses

An inflammasome is a multiprotein complex that contributes to defense against pathogens and repair during inflammatory processes while producing inflammatory diseases under aberrant chronic conditions. Inflammasome assembly triggers caspases’ activation, setting off inflammatory cytokines, including IL-1 activation.

The finding of IL-17 and IL-17-secreting T cells has improved our understanding of the T cell's role in autoimmune and other inflammatory diseases. The Th1 cells were first considered key pathogenic T cells in many autoimmune diseases. However, mice deficient in IFN-γ or IL-12 signaling had exacerbated symptoms in certain autoimmune diseases [58].

Dendritic cells associated with inflammasome hyperactivity boost T lymphocyte activity (Th1/Th17) through increased IL-1β, IL-18, and IL-23 release. IL-18 amplifies Th1 cells’ IFN-γ production and enhances Th1 differentiation while IL-1β promotes Th17 polarization and IL-17 release, triggering a pathological autoinflammatory and autoimmune profile.

Besides, IL-1 and IL-23 (Figure 4) can induce and activate human Th1/Th17 cell differentiation. IL-1 can induce cells of the innate immune system to produce IL-6, which stimulates naïve T cell differentiation to Th17 [59].

6. Conclusions

From a pathogenic perspective, most autoinflammatory and autoimmune diseases share a chronic aberrant immune system activation, which leads to tissue inflammation and damage of varying magnitude in genetically predisposed individuals. IL-1 has grown into a complex, multifaceted family of cytokines with complex regulatory mechanisms and diverse functions in health and disease.

IL-1 and inflammasome are strongly associated with adaptive and autoimmune disorders. The role of the inflammasome-associated IL-1 cytokines family in shaping adaptive immune responses is now well-established regarding the differentiation of Th17 cells and promoting effector functions of Th1 cells and CD8 T cells. In addition, cell lysis triggers inflammasome activation, releasing additional DAMPs and self-antigens, linking autoinflammation and autoimmunity. The contribution of IL-1 and associated molecules to inflammasome regulation needs exploration to improve our understanding of inflammatory diseases.

The relevance of the IL1-related cytokines has outreached classic immunopathology and is a critical bridge to understanding mixed-pattern diseases.

Novel therapeutic intervention strategies may be anticipated after deepening our understanding of inflammatory disorders and the molecular pathways of autoinflammation, autoimmunity, and immune homeostasis regulation.

Data Availability

The data supporting this review are from previously reported studies, which have been cited.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

Rodolfo Kölliker Frers and Tamara Kobiec shared authorship.

Acknowledgments

This work was supported by Grants of CONICET (PIP 0779 2016–2022), the Universidad de Buenos Aires (UBACyT 2017–2022), and FONCyT (PICD 0031 2016-2022), Argentina.

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