Research progress on the neutrophil components and their interactions with immune cells in the development of psoriasis

Abstract Background Psoriasis is an immune‐mediated chronic inflammatory disease, and currently it is widely believed that the IL‐23/IL‐17 axis and Th17 cells play a critical and central role. However, increasing evidence suggests that neutrophils may interact with a variety of immune cells to play an indispensable role in psoriasis. Materials and methods We searched the recent literature on psoriasis and neutrophils through databases such as PubMed and CNKI, and summarized the findings to draw conclusions. Results Neutrophils can promote the development of psoriasis by secreting IL‐23, IL‐17, and cytokines with TH17 cell chemotaxis. Activated keratinocytes (KCs) can attract and activate neutrophils, induce the formation of neutrophil extracellular traps (NETs). KCs can also expose self‐antigens which lead to strong autoimmune reactions. The granule proteins secreted by activated neutrophils can activate IL‐36, which converts vulgaris psoriasis to generalized pustular psoriasis (GPP). Conclusion The function of neutrophils components and the interaction between neutrophils and immune cells play an essential role in the pathogenesis of psoriasis. The aim is to provide a theoretical basis for the exploration of targeted clinical treatments and fundamental research on the pathogenesis of psoriasis.

treatment, which suggests that other factors may be involved in the mechanism of psoriasis development.
Neutrophils are the most abundant cells of innate immunity and the most prevalent white blood cells in the blood of healthy individuals. They play an indispensable role in anti-infective and inflammatory processes through mechanisms such as antigen presentation, reactive oxygen species (ROS) generation, release of granular proteins, formation of neutrophil extracellular traps (NETs), and production and release of cytokines. [11][12][13] Changes in neutrophils within the skin lesions in patients with psoriasis suggest that neutrophils play an important role in the development of psoriasis. KCs, the skin's epithelial cells, release chemokines such as CXCL1, CXCL8, CXCL10, CCL2, CCL3, CCL5, and CCL20. Those chemokines attract neutrophils to psoriatic lesions. 14 Neutrophil-keratinocyte interactions can result in the production of IL-17, which initiates or exacerbates the skin lesions 15 ( Figure 1). Recent studies have found that neutrophils are responsible for the most IL-17 production in psoriatic lesions. 16 Suggesting that neutrophils play a key role in the development of psoriasis. The roles of IL-17/IL-23 axis have been widely reviewed otherwise for psoriasis, 7 we will focus on the new insights on the function of neutrophils and their potential mechanisms of action in interacting with other immune effectors during the pathogenesis of psoriasis in this review. We hope it will give a clue for exploring new treatment strategies for psoriasis in future.

Neutrophil cytokines and psoriasis
Neutrophils, as a type of innate immune cell, are the first to reach the site of inflammation in the early stages of inflammation. Neutrophil lifespan is short, and apoptosis begins after entering the blood for 24 h, but during the period of psoriasis inflammation, the lifespan of neutrophils can be significantly extended. 13 For example, during inflammation, KCs can prolong neutrophil lifespan. 17 The chemokines released by skin KCs can attract neutrophils to migrate constantly to psoriasis lesions and prolong neutrophil lifespan during inflammation. 17 And then, neutrophils produce and secrete IL-17 16   ( Figure 2). The IL-17R, IL-17 receptor, is expressed on monocytes, lymphocytes, fibroblasts, and KCs. 29 IL-22 promotes the proliferation and hyperkeratination of KCs. 30 The function of IL-17A in autoimmune disorders is to promote the release of cytokines, chemokines, and matrix metalloproteinases from tissue cells, 31 and to enhance the production of antimicrobial peptides and chemokines by KCs. 32 IL-17A has been shown to drive the production of IL-1β, IL-6, TNF, and GM-colony-stimulating factor (CSF) by fibroblasts, 33 epithelial cells, 34 and dendritic cells. 35 Among these factors, IL-1β and IL-17A cooperatively promote Th17 cell proliferation 36 ; IL-17A can also induce the expression of chemokines CXCL2 and CCL20. 37 Although neutrophil recruitment is mainly influenced by the CXCL8 chemokine family, 38 IL-17A can induce the release of granulocyte colony-stimulating factor (G-CSF) and GM-CSF to promote the proliferation and survival of neutrophils, 39 which further recruit neutrophiles at the inflammatory site and resulting in a self-amplifying effect ( Figure 1).
Among other diseases comorbid with psoriasis, IL-17-producing neutrophils have also been observed. IL-17+ neutrophils were found in atherosclerotic plaques. 40 These IL-17+ neutrophils may be one of the mechanisms behind the comorbidity of psoriasis with other diseases. Such as G-CSF can induce neutrophils to produce CXCL5 48 and CXCL2 49 . Under the stimulation of microorganisms or their derivatives such as lipopolysaccharides, neutrophils can produce CCL20 and CCL19. 50 IL-23 can promote the release of G-CSF and indirectly promote neutrophil production by neutrophil. However, there is currently no evidence to confirm that IL-23 can directly promote neutrophil production of chemokines. Further exploring whether IL-23 can directly promote neutrophil to produce chemokines, which deserves a further study to clarify.

The role of neutrophil granule proteins in Psoriasis
The composition of neutrophil granule proteins is relatively complex and can be divided into three major categories, including primary azurophilic granules (myeloperoxidase (MPO) etc.), secondary specific granules, and gelatinase granules (matrix metallopeptidase 9 (MMP-9) etc.). 51 Different particles have different functions, and those related to psoriasis include MPO, various neutrophil proteases, MMP-9, etc.
The granule proteins of these neutrophils promote the occurrence and development of psoriasis by activating cytokines released by other cells or damaging the VECs. Elastase, proteinase 3, and tissue proteinase G are all part of the neutrophil azurophilic granules. They not only activate the IL-36 precursor into the more forms of IL-36β and IL-36γ, but also inactivate IL-36Ra through their elastase, further enhancing inflammation. 52 In addition, it promotes the overproliferation of KCs in psoriatic lesions by activating the EGFR pathway, 11 as well as promoting the secretion of type I IFN by myeloid dendritic cells. 53 The proteinase 3 and tissue proteinase G can respectively activate neutrophils to produce chemokines CXCL-8 and CXCL-5. 54 This will cause self-amplification of neutrophil chemotaxis.
MMP-9 belongs to the specific granules of neutrophils and is involved in cell apoptosis, innate immunity, and kidney development, and also has the function of limiting bacterial proliferation. 55 The further study demonstrates that MMP-9 can disrupt the tight junctions and cytoskeletal integrity of endothelial cells, damage the vascular barrier function, and significantly increase vascular permeability, further enhancing inflammation. 56 Recently, it was found that neutrophils with MPO gene defects have decreased ability to produce NETs. 57 One possible mechanism is that the formation of NETs requires the participation of ROS. However, the same study also showed that the reduction of MPO leads to an increase in the activity of the serine protease (containing elastic enzyme, proteinase-3, and cathepsin G) of neutrophils, which may result in the activation of more IL-36.
And the expression of CD47 on the cell membrane of MPO-deficient neutrophils is increased, while CD47 can inhibit the phagocytosis of monocytes on neutrophils. 58 Therefore, MPO deficiency may be the cause of worsening IL-36-mediated GPP.

Generation and NETsis of NETs
NETs are fibrous networks released by neutrophils that contain various components such as neutrophil granule proteins, LL-37, RNA, and cytokines. 59,60 Initially, NETs were believed to play a role in trapping and killing extracellular pathogens. 61 However, NETs are not only produced during states of infection but can also be produced in response to immune complexes and cytokines such as IL-8 and IL-23. 62 Indicating that NETs not only have anti-infective effects but also play a role in autoimmunity. Eosinophils, mast cells, neutrophils, macrophages, and Th17 cells can all produce extracellular traps. 63 Compared to healthy controls, patients with psoriasis have higher levels of NETs in their skin lesions and peripheral blood. 63 Indicating that NETs play an important role in psoriasis.

The formation of extracellular traps by neutrophils is called
NETosis. 64 There are three modes of NETosis, the first of which is suicidal. Neutrophils triggered by activators (such as carnitine, autoantibodies or uric acid crystals) 64 can induce ROS activation. Thus ROS activating peptidyl arginase deaminase 4, which leads to chromatin depolymerization. Neutrophil elastase and MPO are transferred to the nucleus to promote chromosome decondensation and nuclear membrane rupture. Ultimately, neutrophil death, and the release of NETs into the extracellular space. 64 The second mode, independent of ROS, is triggered by TLR and complement C3 receptors. It involves nuclear chromatin decondensation and nuclear membrane rupture, as well as the release of nuclear DNA. However, after this type of NETosis, neu-trophils are still able to phagocytose pathogens, and neutrophil lifespan is not affected by DNA loss. 65 The third mode of NETosis also depends on ROS, but results in the release of mitochondrial DNA. 66 The uncontrolled release of NETs may contribute to various diseases such as psoriasis, systemic lupus erythematosus, 67 rheumatoid arthritis, 68 cardiovascular disease, inflammatory bowel disease, 69 etc.
Therefore, NETs may not only be mechanisms of psoriasis but also mechanisms of comorbidities.

Functions of NETs
NETs contain MMP-9, 11 , neutrophil elastase, MPO, and cathepsin G, 60 as well as proteases 3 and LL-37. 70 In various autoimmune diseases, such as rheumatoid arthritis 71 and systemic lupus erythematosus, 72 NETs also contain self-antigens, which can be recognized by immune cells to induce autoimmunity. 73 The antibacterial peptide (LL-37) can also act as a self-antigen, 65 and is found in many cells, especially in KCs and neutrophils, 74  This indicates that NETs can promote the onset and maintenance of psoriasis through multiple pathways.

The interaction of neutrophils with other immune cells
In traumatized or microbially infected skin, mast cells recognize viruses, bacteria, and other pathogens through TLRs. 84 This may lead to mast cells releasing TNF-a, IL-17, and CXCL2 through degranulation or MCETs. 16  skin. And may be one mechanism of the Koebner phenomenon in psoriasis patients. Interactions also exist between IL-17-producing T cells and neutrophils, as IL-17-producing T cells can produce cytokines that promote neutrophil development, recruitment, and survival. 13 KC in the skin has antigen-presenting function. 86 Streptococcus is believed to be associated with psoriasis, 87  DsRNA can come from viruses or from the organism. 94 Perhaps dsRNA is a autoantigen that can induce psoriasis. Therefore, perhaps in the early stage, psoriasis is independent of Th17. As keratinocytes produce IL-23, mast cells originally stationed in the skin tissue will release IL-17 first. 16 Or in the early stages of inflammation, neutrophils arrive at the skin first, causing a series of reactions. This is because KCs simultaneously express and release both neutrophil chemokines and IL-23, allowing neutrophils to be chemotactically activated. Studies have shown that co-incubation of KCs and neutrophils for 4 hours can induce neutrophils to produce IL-17 and IL-22. 15 We can speculate that IL-23 activates the IL-23R on neutrophil membranes, causing neutrophils to release IL-17. And IL-17A is one of the most pro-inflammatory cytokines in the IL-17 family, which binds to the receptor IL-17R on KCs, leading to an increase in the production of cytokines such as TNFα, IL-1, IL-8, and IL-6 95 (Figures 1 and 2). Neutrophils can also induce KC proliferation and keratinization by producing IL-22. 30

CONFLICT OF INTEREST STATEMENT
The authors have no relevant financial or nonfinancial interests to disclose.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.