NETs, which are composed of decondensed chromatin forming a reticulated DNA structure with pores of approximately 200 nm, are surrounded by nuclear proteins (13). These proteins can be classified into three categories: histones, granule proteins, and cytoplasmic proteins. Granule proteins mainly include neutrophil elastase and myeloperoxidase. Cytoplasmic proteins include representatives such as S100 calcium-binding proteins A8, A9, and A12, as well as actin and α-actin (14–16).

The formation of NETs can involve two main mechanisms, namely vital NETs and suicidal NETs (17). Suicidal NETosis is the release of DNA networks by neutrophils through apoptosis, in which the nucleus is discharged into the surrounding environment (18). When neutrophils perceive a stimulus, the stimulus directly activates the protein kinase C (PKC) and Raf-MEK-ERK-MAP kinase pathways. Next, the activation of MAP kinase will initiate the formation of the NADPH oxidase complex (19, 20), leading to the rapid generation of reactive oxygen species (ROS) (21). Neutrophil elastase (NE) and myeloperoxidase (MPO) contribute to the enhancement of nuclear membrane permeability and the promotion of chromatin formation (22), as well as in the nucleus, where NE and MPO can facilitate the digestion of histones H2b and H4 through synergistic effects (23, 24). At the same time, ROS may increase Ca²⁺ in the cytoplasm by disrupting the endoplasmic reticulum or mitochondrial membrane, thereby activating peptide-based arginine deaminase 4 (PAD4) (25). Then, PAD4 modifies histone H3 by converting arginine to citrulline, leading to chromatin depolymerization (26). During nuclear rupture, citrulline histones (26, 27) and nuclear DNA (28)are released together. The released DNA is further decorated by granular (NE and MPO) (29) and cytosolic proteins (Calpain) (30). The increase of intracellular ROS can also activate receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain like protein (MLKL), promoting membrane rupture (31, 32).

Vital NETosis is formed by neutrophils passing through the cell membrane and releasing DNA and proteins into the surrounding environment to form NETs (33). At first, PMA stimulates neutrophils, leading to rapid activation of intracellular NADPH oxidase and ultimately increasing ROS (19, 34). When DNA dissociated from chromatin leaves the cytoplasm through vesicles, it can be modified by granular proteins (NE, MPO, and PR3) (29, 34). Subsequently, neutrophils maintain activity and exert further functions (35), using the increased intracellular ROS to mobilize the cytoskeleton to transport particles and mitochondria (36), and using ATP to transport particles to the outside of neutrophils through actin (37).

There is a higher likelihood of NET formation in neutrophils in individuals with psoriasis than in healthy individuals (38). Furthermore, it has been observed that there may be alternations in NETs during the onset of the disease. A recent study suggests that NETs in individuals with psoriasis exhibit an increased presence of proteins, including inflammatory mediators and antimicrobial proteins such as histone, myeloperoxidase, neutrophil elastase LL37, and RNA-LL37 (39). These proteins are believed to play a role in the inflammatory process that contributes to the development of skin lesions.

Psoriasis, as an inflammatory skin disease, is characterized by the infiltration of neutrophils. In response to inflammatory signals, circulating neutrophils are recruited to an inflammatory site and become activated. These activated neutrophils produce and release large amounts of ROS as part of their antimicrobial activity. Two key enzymes involved in the respiratory burst and subsequent ROS production are NADPH oxidase (NOX2) (51) and MPO (52). Research has shown that neutrophils from psoriasis patients have higher MPO and NOX2 activity, leading to increased ROS release compared with neutrophils from healthy individuals (53, 54). An imbalance in ROS production, either through overproduction or insufficient clearance of ROS, can result in oxidative-stress-related dysfunctions.

In patients with psoriasis, neutrophils are pre-activated and form NETs within psoriatic lesions. These NETs are increased in blood samples and correlate with the severity of psoriasis. NETs create a highly immunogenic environment and are involved in the initial and maintenance phases of psoriasis. They are enriched in RNA, particularly LL37. When RNA binds to LL37 and subsequently stimulates neutrophils, this can lead to the release of IL-8 and a moderate shedding of CD62L (41, 42). The data suggest that the involvement of neutrophils and their activation in psoriasis highlight their significant role in the pathogenesis of the disease.

One of the central features of psoriasis is the dysregulated crosstalk between keratinocytes and immune cells. Activated keratinocytes in psoriatic skin release pro-inflammation, IL-1, TNF, and IL-6. These cytokines not only amplify the inflammatory response but also induce the production of chemokines, which attract immune cells to the sites of inflammation. These cytokines activate dendritic cells, which in turn produce the cytokines IL-12 and IL-23, leading to the differentiation of TH1 and TH17 cells.

As shown in Figure 1 , in the context of NETosis, keratinocytes have been shown to be with NETs and their components. Studies have demonstrated that keratinocytes can internalize NETs and take up antimicrobial peptides, such as LL37 and human beta-defensin 2 (HBD2), present in these structures (55).

NETs, including psoriatic NETs, have been shown to induce HBD-2 mRNA production in epidermal keratin-forming cells, thereby promoting the expression of HBD-2 (56). Moreover, it is well-established that HBD-2 is primarily expressed in keratinocytes (57–59). In line with previous studies, Gambichler et al. reported elevated levels of HBD-2 in psoriatic skin compared with healthy controls (60). The induction of HBD-2 expression in keratinocytes by NETs suggests a potential mechanism through which neutrophils and keratinocytes contribute to the inflammatory cascade observed in psoriatic skin.

Similarly, Kanda et al. shed light on the association between LL37 levels and psoriasis. Their findings revealed significantly higher levels of LL-37 in the sera of patients with psoriasis than in normal subjects. Interestingly, the researchers also observed a correlation between serum LL-37 levels and HBD-2 levels in patients (61). HBD-2 is believed to contribute to psoriasis development by acting on neutrophils.

Taken together, the interaction between keratinocytes and neutrophils, mediated by factors such as HBD-2 and LL37, plays a role in promoting inflammation and NETosis in psoriasis. Further studies of HBD-2 may provide valuable insights into the pathogenesis of psoriasis and potential therapeutic targets.

Mast cells (MCs) play a crucial role in immune modulation through the release of various pro- and anti-inflammatory mediators (62). The role of mast cells in psoriasis has been extensively studied, with investigations indicating a significant increase in the number of mast cells at psoriatic lesions compared to healthy individuals (63). In the context of psoriasis, MCs contribute to the inflammatory state by producing caspase-1 and chymotrypsin. These enzymes play a crucial role in activating immature IL-1β into mature active IL-1β (64). The production of IL-1β by MCs further amplifies inflammation and leads to an increase in the number of infiltrating neutrophils in response to protease release (65).

Neutrophils release LL37-RNA through the NETosis process. This LL37-RNA can be recognized by MCs triggering their activation and the subsequent production of IL33. IL33 then binds to ST2R on the surface of macrophages, stimulating the production of IL-36 by macrophages.

Dendritic cells (DCs) are specialized antigen-presenting cells that play a crucial role in the immune system. They act as a bridge between innate and adaptive immunity by capturing, processing, and presenting antigens to T cells. They are a heterogeneous population of cells comprising different subpopulations, including plasmacytoid DCs (pDCs), classical/myeloid DCs (cDCs/mDCs), and monocyte-derived dendritic cells (moDCs) (66, 67). cDCs are a major subset of DCs specialized in presenting antigens to CD4+ helper T cells. Through this antigen presentation, effector T cells including Th2 and Th17 cells are activated (68). pDCs mainly produce a large amount of IFN-α and IFN-β, which can also directly activate T cells through stimulation (69). moDC can effectively express TNF- α and inducible nitric oxide synthase (iNOS), and iNOS-mediated NO production inhibits T cell proliferation (70).

In psoriasis, studies have shown that the number and activity of pDCs are increased in areas of skin lesions. These pDCs are responsible for producing interferon in psoriatic plaques (71). Interferon production by pDCs in psoriasis may trigger an immune response that exacerbates symptoms. The overproduction of interferon can lead to the abnormal proliferation of skin cells and inflammation, ultimately resulting in the formation of typical psoriatic lesions. Recent studies have also found that the overexpressed antimicrobial peptide LL37 in the skin of patients with psoriasis can form a new complex with self -DNA. These complexes can trigger TLR9 in dendritic cells, specifically pDCs (72, 73). When neutrophils capture pathogens and release NETs, the DNA-LL37 complexes within these NETs can be captured by dendritic cells, particularly pDCs. Dendritic cells then process these antigens and present them to T cells, initiating a specific immune response. This immune response involves the production of TNF-α and IL-6 (41, 73). These data indicate that the interaction between DCs and NETs is involved in the pathogenesis and progression of psoriasis.

When grouping DCs in the blood of psoriasis patients, it can be found that not only the skin but also the mDCs in the blood have Th1 polarization and Th1/Th17 recruitment abilities (74). This discovery provides a possible blood testing target for the diagnosis of psoriasis. In addition to directly stimulating Th1 polarization, mDCs can also co-culture with inflammatory polymorphonuclear leukocytes (PMNs) to form NETs, from which they can absorb antigens. This process potentially allows for antigen processing and presentation, indirectly stimulating Th1 polarization. Reducing mDCs can block the occurrence of NETosis. In a mouse model, mDCs activated by NETs can induce antineutrophil cytoplasmic antibody (ANCA) and autoimmune responses (75). When psoriasis patients experience renal organ damage, ANCA positivity may occur. mDCs may work together with NETs in this situation, exacerbating the progression of the disease.

Monocytes and macrophages are key components of the immune system and play key roles in immune defense, surveillance, and self-stabilization. They are capable of phagocytosing and eliminating intracellular parasites, foreign bacteria, and mutated tumor cells, as well as their own senescent and abnormal cells. Macrophages can differentiate into different cell subpopulations, including two representative subpopulations, M1 and M2, based on the stimulation of different stimuli and the production of different cytokines.

Studies on mouse models of psoriasis have demonstrated a strong correlation between macrophages and the severity of psoriasis (76, 77). Pathological sections of skin lesions from psoriasis patients have also shown the presence of aggregated macrophages (78). When staining the skin lesions of psoriasis patients, it can be observed that CD68⁺iNOS⁺M1 increase and CD68⁺CD163⁺M2 decrease (79). Increased M1 polarization in psoriasis patients is associated with increased disease severity (80). In addition, the number of CD68⁺ (81) and CD163⁺ macrophages expressing TNF-a in the dermis (82) also increased in human skin with psoriasis lesions (82). Activation of the NLRP3 inflammasome by macrophages can also be involved in psoriasis (83). Research has shown that NLRP3 may be a promising therapeutic target for the treatment of psoriasis (84). The method of inhibiting NLRP3 inflammasome activation can alleviate psoriasis inflammation (85).

In this context, when dying neutrophils release LL37 through NETosis, the P2X7 receptor on monocytes is activated. This activation triggers the release of inflammatory vesicles and the production of IL-1β (32, 33). Similarly, when LL37-DNA complexes are released, the TLR9 receptor on monocytes is activated, leading to the release of IL-6, IL-12, IL-23, and TNF-α (20). These cytokines, including those produced by pDCs, can further stimulate monocytes/macrophages to produce IL-23. The accumulation of IL-23 at the site of a skin lesion can lead to the production of additional cytokines by macrophages, including IL-17A, IL-22, and IFN-γ, in addition to TNF-α (86).

It is widely recognized that IL-23 plays a crucial role in maintaining the activation of Th17 cells (87). IL-23 promotes the production of IL-17A by Th17 cells, which in turn leads to the recruitment and activation of neutrophils (88). This cytokine cascade contributes to the inflammatory response observed in psoriasis. In in vitro experiments, the percentage of CD3+CD4+IL-17+ (Th17) cells among T cells is significantly higher in the presence of NETs compared to the control group without NETs. Act1 is a key mediator for IL-17 signal transduction (89). In the presence of NETs, the downstream key factor Act1D10N of the psoriasis susceptibility gene TRAF3IP2 mutation is enhanced, further inducing the production of Th17 cells (90). In summary, these results indicate that NETs are of great significance in the immunogenetic study of neutrophil-induced human Th17 cells and psoriasis.

Studies have indicated that NETs are abundant in environments rich in myeloid cells and memory T cells. This suggests that NETS play a role in inducing the formation of other immune cells (91, 92). Experimental findings by Evans et al. support this notion, demonstrating a link between NETs and Th17 responses in psoriasis patients. The researchers further explored this interaction, showing that NETs can induce the differentiation of memory CD4 T cells into LL37-specific Th17 cells (93). These memory T cells not only secrete IL-17A but also express IL-17F and RORC, which stimulates keratinocytes to secrete LL37 (90). Subsequently, IL-6/IL-23 secreted by monocytes induces LL37-specific Th17 cells to migrate to the epidermis, where they recognize the LL37 expressed by keratinocytes (94). This mechanism creates an immune amplification effect. Th17 cells identify the synthesis of LL37 as a T-cell antigen, and their responses are further fueled by a synergistic interaction of IL-1, IL-6, and IL-23 (34, 35).