Neutrophils in Psoriasis

Abstract

Neutrophils are the most abundant innate immune cells. The pathogenic roles of neutrophils are related to chronic inflammation and autoimmune diseases. Psoriasis is a chronic systemic inflammatory disease affecting ~2-3% of the world population. The abundant presence of neutrophils in the psoriatic skin lesions serves as a typical histopathologic hallmark of psoriasis. Recent reports indicated that oxidative stress, granular components, and neutrophil extracellular traps from psoriatic neutrophils are related to the initial and maintenance phases of psoriasis. This review provides an overview on the recent (up to 2019) advances in understanding the role of neutrophils in the pathophysiology of psoriasis, including the effects of respiratory burst, degranulation, and neutrophil extracellular trap formation on psoriatic immunity and the clinical relationships.

Keywords: degranulation; immunity; neutrophil extracellular traps; neutrophils; psoriasis; respiratory burst.

Figure 1

The offensive mechanisms of neutrophils in inflammation. In the activated neutrophils, respiratory burst, degranulation, and the formation of neutrophil extracellular traps (NETs) are the main mechanisms responsible for inflammation. During the respiratory burst, neutrophils utilize oxygen to produce reactive oxygen species (ROS) such as superoxide (${\text{O}}_2^{-}$), peroxide H₂O₂ or hypochlorous acid (HOCl) by activating NADPH oxidase (NOX2) and myeloperoxidase (MPO). As activation processes are triggered by diverse stimuli, neutrophils mobilize different granules including azurophilic granules, specific granules, gelatinase granules, and secretory vesicles. Subsequently, neutrophils degranulate and release various granular compounds of which neutrophil elastase (NE), MPO, proteinase 3, LL37, and lipocalin 2 play an important role in the pathogenesis of psoriasis. NETs are novel and pivotal components of neutrophils composed of extruded sticky and decondensed chromatin decorated with many antimicrobial compounds, such as histones, MPO, NE, and cathepsin G. The formation of NETs is involved in complicated inflammatory reactions and contributes to the pathogenesis of psoriasis. MPO, myeloperoxidase; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NE, neutrophil elastase; NET, neutrophil extracellular trap; NOX2, NADPH oxidase.

Figure 2

Role of neutrophils in psoriasis. Various and diverse endogenous and exogenous impulses such as antigens, trauma, infection, or emotional stress can trigger the complex immune reactions leading to psoriasis. The interplay of neutrophils, dendritic cells, and T cells bridges the innate immune and adaptive immune systems. T cells and keratinocytes release chemokines, such as IL-17, CXCL1, CXCL2, and CXCL8, that mediate the recruitment of neutrophils. Circulating neutrophils migrate to the psoriatic lesions and induce respiratory burst, degranulation, and formation of NETs, thereby contributing to the immunopathogenesis of psoriasis which involves T cell imbalance, keratinocyte proliferation, angiogenesis, and auto-antigen formation. Neutrophils from patients with psoriasis have enhanced NOX2 and MPO activity and augmented respiratory burst. MPO also participates in generating oxidative stress and upregulating degranulation. The accumulated oxidative stress produced by neutrophils could stimulate the antigen-presenting cells pDCs via TLR receptors 7 and 9 which stimulate antigen-specific CD8+ T cells (memory T cells in dermis and naive T cells in lymph node) to release cytokines, chemokines, and other innate immune mediators. These T cells may also migrate to epidermis and trigger local inflammation and keratinocyte proliferation via MHC I receptor of keratinocytes. Production of IFN-α and IFN-β by pDCs then stimulates mDCs to secrete pro-inflammatory mediators such as TNF, IL-12 and IL-23. Proteinase 3 released from neutrophils cleaves pro-IL-36 to activated IL-36 cytokine amplifying the response of mDCs. TNF, IL-12, and IL-23 play an important role in the initiation of the Th1, Th17, and Th22 cells immune response in lymph node, leading to a secretion of various cytokines and chemokines. IL-1 is further amplifying Th17 response while TNF and IFN-γ is creating a back loop to mDCs activation. Th17 activation then leads to the production of IL-17 activating neutrophils and keratinocytes via IL-17 receptors which generates profound IL-17 response. Keratinocytes produce TNF and CCL20, a chemotactic for T cell and DCs. Neutrophils degranulate and release MPO, NE, proteinase 3, cathepsin G and lipocalin. Proteinase 3 cleaves and converts the resting TNFα located in membrane of epithelial cells (mTNFα) to an activated state called soluble TNFα (sTNFα). Proteinase 3 also contributes to the formation of the LL-37 which serves as autoantigen. The chromatin of NETs (DNA) combined with LL-37 have a profound role in the initiation and maintenance of immune response in psoriasis. NETs further supply IL-17 and induce Th17 cells to release more IL-17, which plays a decisive role in the maintenance of psoriasis. These processes participate in the psoriasis complex inflammatory reactions and lead to the escalation of local psoriatic tissue inflammation. IL-22 contributes to the formation of characteristic psoriatic skin lesions including epidermal hyperplasia and acanthosis (thickening of skin). The activation of the following transcription factors promote TNF and IL-17 production and formation of downstream amplification loops in psoriasis: the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) family, nuclear factor-κB (NF-κB) and cyclic AMP. Furthermore, the activation of endothelial cells induces vascular proliferation, angiogenesis and the expression of adhesion molecules in the endothelium to recruit additional inflammatory cells into the skin such as mast cells and macrophages contributing to the pathogenesis of psoriasis. CCL, CC-chemokine ligand; CXCL, chemokine (C-X-C motif) ligand; IL, interleukin; IFN, interfenon; MHC I, major histocompatibility complex class I, MPO, myeloperoxidase; NET, neutrophil extracellular trap; NOX, NADPH oxidase; NE, neutrophil elastase; pDCs, plasmacytoid dendritic cells; mDCs, myeloid dendritic cells; TLR, Toll-like receptor; TNF, tumor necrosis factor.