Itch is the most common symptom seen in dermatology clinics1 and can be divided into 2 categories: acute itch (lasting <6 wk) and chronic itch (lasting >6 wk)2. Chronic itch impairs patient quality of life3, hinders productivity, and interferes with a variety of daily activities4.
Itch signaling originates in the epidermis and is transmitted to the central nervous system by both the histaminergic and nonhistaminergic pathways5,6. These pathways have their own respective receptors and cutaneous nerve fibers. Dynamic interactions between keratinocytes, immune cells, and sensory nerve endings strongly influence the sensation of itch7,8. Among these factors, immune cells are one of the most important factors in the elicitation of itch. Immune cells can release mediators that induce itch directly by stimulating pruriceptors or indirectly through activating other cells to secrete pruritogens9. The most common immune cells associated with itch are mast cells, eosinophils, and T cells. However, neutrophils are also capable of producing and releasing a variety of pruritogens.
In this review, we summarize the pruritogens that neutrophils produce and release (Fig. 1) and the pruritic diseases in which neutrophils may induce or mediate itch (Table 1).
Neutrophils are the dominant circulating leukocytes and have an average diameter of 7–10 μm with a lobed nucleus and granular cytoplasm. The half-life of neutrophils is 13–19 hours under homeostasis but can be prolonged under inflammatory conditions or when interacting with other cell types10–12. Neutrophil granules contain proinflammatory proteins and can be divided into 3 groups: (1) primary (azurophilic) granules contain potent hydrolytic enzymes (eg, elastase and cathepsin S) and myeloperoxidase; (2) secondary (specific) granules contain lactoferrin; and (3) tertiary (gelatinase) granules contain matrix metalloproteinase 913,14.
Neutrophils are involved in both innate and adaptive immunity and in inflammation15,16. Neutrophils exert their functions via phagocytosis, the formation of neutrophil extracellular traps, the release of granules and secretion of a variety of cytokines and chemokines17,18, and by acting as antigen presenting cells19,20.
Pruritogens associated with neutrophils
Histamine is the most studied pruritogen. Histamine is produced and secreted mainly by mast cells and basophils21,22. Recently, neutrophils were also reported to release histamine in response to lipopolysaccharide stimulation and to sensitization with antigen-specific IgE23,24. However, the significance of neutrophil-derived histamine in itch is still unknown.
Protease-activated receptors (PARs), which have 4 known subtypes (PAR-1 to PAR-4), represent a unique type of G-protein coupled receptor in that PARs are activated through the proteolytic cleavage of their own extracellular N-terminus25. Both endogenous and exogenous proteases [eg, tryptase, trypsin, cathepsins, kallikreins, mucunain (found in cowhage), and proteases from dust mites] induce nonhistaminergic itch via mainly PAR-2 and likely also PAR-426. In atopic dermatitis (AD) patients, expression of PAR-2 on nerve fibers in the skin is markedly enhanced, and intralesional application of PAR-2 agonists induces prolonged itch sensation27.
Human neutrophils possess several types of proteases, including elastase28, which can activate PAR-229. Neutrophil elastase is stored in neutrophil cytoplasmic azurophilic granules30 and is involved in inflammation through PAR-2 and transient receptor potential vanilloid 431. There are reports that indicate the involvement of neutrophil elastase in itch. For example, the release of elastase from neutrophilic azurophilic granules correlated with the degree of ivermectin-induced side effects including itch32. One paper reported that an anaphylactoid reaction with generalized pruritus caused by ioxaglate was accompanied by an increased number of neutrophils and high levels of neutrophil elastase in the peripheral blood33. Itch scores in patients with palmoplantar pustulosis (PPP) decreased in parallel with the number of infiltrating cells expressing neutrophil elastase34.
Cathepsin S is an endogenous cysteine protease that activates PAR-2 and PAR-4 and elicits itch in humans35. Cathepsin S resides in human neutrophils in addition to keratinocytes36–38. In seborrheic dermatitis, lesional levels of cathepsin S and PAR-2 are elevated and correlate with the intensity of itch39.
Prostaglandin E2 (PGE2)
PGE2 is one subtype of eicosanoids which is synthesized from arachidonic acid by phospholipase A2, cyclooxygenase, and PGE2 synthase40. Intradermal injection of PGE2 induces itch that can be alleviated by administering antihistamines. In addition, intradermal injection of PGE2 with histamine elicited stronger itch41–43. Thus, PGE2 is thought to potentiate histamine-induced itch. Human neutrophils are able to produce PGE244,45; however, the significance of neutrophil-derived PGE2 in itch has not yet been elucidated.
Leukotriene B4 (LTB4)
Leukotrienes are another class of eicosanoids and are generated from arachidonic acid by 5-lypoxygenase46. Intradermal injection of LTB4 induces itch in mice47, but there is no direct evidence of LTB4 inducing itch in humans. However, LTB4 has been implicated in the pathogenesis of allergic pruritic diseases such as AD, psoriasis, and Sjögren-Larsson syndrome48–50. LTB4 is a potent chemoattractant for neutrophils44,51. Human neutrophils are able to generate LTB4 and express its receptor BLT1. Mechanical injury to human or mouse skin (scratching or tape stripping) causes dermal infiltration of neutrophils and increases neutrophil-derived LTB4 in the dermis. LTB4 prompts a further influx of neutrophils and BLT1-expressing T cells. This pathway may result in skin inflammation and itch sensation52.
S100A8 (calgranulin A) and S100A9 (calgranulin B) are members of the S100 protein family and are expressed mainly by neutrophils in addition to keratinocytes and macrophages53,54. S100A8 and S100A9 form homodimers and heterodimers. Both forms exhibit proinflammatory activities and play a role in inflammatory diseases (eg, AD and psoriasis)55. Genomic studies reveal that S100A8 and S100A9 are also elevated in psoriasis and AD skin, especially in the itchy lesions of these diseases56. Both the AD and psoriasis feature neutrophilic infiltration in the lesional skin57,58. Although how S1008A and S100A9 may promote itch is unclear, neutrophils may be involved in itch partially through secreting these proteins.
Neutrophils and pruritic skin diseases
Psoriasis is a common chronic inflammatory skin disease, and itch is a prevalent feature of psoriasis that affects the quality of life59. One of the histologic hallmarks of psoriasis is neutrophilic infiltration into the lesional skin. Neutrophils play a major role in the pathogenesis of psoriasis60,61. Expression levels of neutrophil elastase62 and LTB449,50,63,64 are upregulated in the lesional skin of psoriasis, suggesting these mediators may be involved in psoriatic itch.
In psoriatic skin lesions, there are a substantial number of neutrophils (in addition to lymphocytes and macrophages) expressing the gamma-aminobutyric acid (GABA)A receptor. In addition, there is a positive correlation between itch and GABAA receptor-positive infiltrating cells in the psoriatic skin65. Thus, the GABA ligand-receptor interaction involving neutrophils may also be implicated in psoriatic itch.
PPP is a chronic inflammatory skin disease. PPP features recurrent sterile pustules mainly on the palms and soles. PPP is considered a variant of psoriasis66. Itch can be associated with these lesions. Neutrophils are involved in the pathogenesis of PPP, and are present in the infiltrate of PPP lesions67. After treatment, the number of infiltrating neutrophils and neutrophil elastase-expressing cells dramatically decreased while itch intensity and skin inflammation improved34. Thus, it is plausible that neutrophil elastase may be involved in PPP itch.
The roles of neutrophils in AD are still unclear. However, in AD, the levels of interleukin (IL)-18 and IL-33, both of which have the ability to activate neutrophils, are increased68,69, and a significant number of neutrophils infiltrate in the lesional skin57. Gene expression of S100A8 and S100A9, which is generally secreted by neutrophils, macrophages, and keratinocytes, is upregulated, especially in itchy lesion56,70. In addition, S100A8 and S100A9 modulate innate immunity partially through a binding Toll-like receptor 471, which activates neutrophils72. Toll-like receptor 4 is reported to be involved in the pathogenesis of AD73,74. Collectively, neutrophils may play a role in AD itch possibly through secreting S100A8/9.
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin
In patients with BCC or SCC, the degree of neutrophil infiltration is associated with an increased prevalence and intensity of itch75. Eosinophils are also associated with itch; however, it is unclear whether neutrophils, eosinophils, or both contribute to itch in malignancy. Neutrophils in the tumor environment (tumor-associated neutrophils) are believed to be partially involved in tumor progression through elastase production and secretion76,77. In a mouse model of skin cancer, inhibition of neutrophil elastase suppressed the development of ultraviolet B-indiced or chemical-induced SCC78. In humans, elastase-expressing polymorphonuclear cells are often found in the vicinity of cutaneous SCC79. Thus, neutrophils may be associated with an itch in malignant skin tumors through the secretion of neutrophil elastase.
Bullous pemphigoid (BP)
BP is an autoimmune blistering disease. BP features edematous erythematous macules and multiple tense bullae with severe pruritus. The primary aims of BP treatment are to control skin eruptions and to minimize itch80.
The pathogenesis of BP is unsettled, but autoreactive antibodies against BP180 and Th2 immune responses are thought to play a role. The Th2-related pruritogenic cytokine IL-31 is a candidate factor for BP itch. IL-31 levels in serum and blister fluid are elevated, and infiltrating eosinophils are possible IL-31 producers81,82.
Another explanation for BP itch is LTB4 and neutrophil elastase. Histologic features of BP include subepidermal bullae containing eosinophils and/or neutrophils and a dermal infiltration of eosinophils and/or neutrophils in skin lesions83. Infiltration of eosinophils and neutrophils may be prompted by Th17 immunity—which is involved in the attraction of neutrophils and eosinophils—and by LTB4, a potent granulocyte chemoattractant. This is supported by the following: a number of IL-17(+) Th17 cells infiltrate in the BP lesions84–86, BP skin blister fluid contains a high level of LTB4, and LTB4 drives neutrophil entry into the skin in a mouse model of BP87. In addition, a large number of infiltrating neutrophils express elastase, and neutrophil elastase is likely responsible for blister formation in human BP83,88. Neutrophil elastase and LTB4 can induce itch, and both of them may contribute to itch in BP.
Dermatitis herpetiformis (DH)
DH is an extremely itchy autoimmune bullous disease. The prevalence of DH is greater in whites, and about 90% of DH patients have gluten-sensitive enteropathy89. Skin manifestations of DH are characterized by a blistering, intensely pruritic papulovesicular rash predominantly located on the elbows, forearms, knees, scalp, and buttocks90. Histologically, these lesions display a neutrophilic and eosinophilic infiltrate. Similar to in BP, IL-17 may play a role in activating and recruiting neutrophils in DH91. In addition, IgA deposition in the papillary dermis under direct immunofluorescence examination is another hallmark of DH90.
The factors responsible for itch in DH are unclear, but serum and skin levels of itch-related cytokine IL-31 from DH patients are high82. Another candidate is elastase from the high number of infiltrating neutrophils. Higher levels of elastase activity are present in blister fluids from DH compared with those from BP, and neutrophil elastase is believed to play a role in blistering formation in DH92. Neutrophil elastase may interact with PAR-2 and evoke itch, but this hypothesis needs further examination.
Chronic prurigo and prurigo nodularis
Chronic prurigo is a distinct disease that is defined by the presence of pruritus lasting >6 weeks, frequent scratching, and multiple localized or generalized pruriginous skin lesions93. Prurigo nodularis is a type of chronic prurigo and features pruritic firm hyperkeratotic nodules93. In the lesions of prurigo nodularis, a significant number of neutrophils and eosinophils infiltrate in the dermis compared with lichen simplex, another pruritic disease94. However, the deposition of neutrophil elastase is minimal95. The significance of neutrophils in the pathogenesis of itch in chronic prurigo needs further examination.
The definition of subacute prurigo is not well established, but it features long-lasting, urticarial plaques or papules with the debilitating itch. “Papular dermatitis” and “urticarial dermatitis” may also refer to subacute prurigo96–98. In the lesions of subacute prurigo, there is an infiltrate consisting of CD15(+) neutrophils, CD8(+) T cells, and CD68(+) macrophages99. In a mouse model of subacute prurigo, a larger number of neutrophils are detected in the lesional skin100,101; however, how neutrophils are involved remains to be elucidated.
Prurigo pigmentosa (PP)
PP, which was first described by Nagashima and is now known as Nagashima disease, is an uncommon inflammatory skin disease of unknown etiology102,103. In the acute stage, PP features urticarial and severely pruritic papules or papulovesicles appearing in a reticular pattern typically on the upper trunk. In the chronic stage, reticulated hyperpigmentation appears103–105. Histologically, massive neutrophilic infiltration in the upper dermis with spongiosis, vacuolar change, and dyskeratosis of the epidermis is apparent104,106. Drugs acting on neutrophils [eg, colchicine, minocycline, doxycycline, and diaminodiphenyl sulfone (Dapsone)] are effective treatments for PP107; this suggests that there is a role of neutrophils in the pathogenesis of PP.
Neutrophils are capable of producing and secreting a variety of pruritogens. Hence, neutrophils may be involved directly or indirectly in itch in various diseases, such as psoriasis, PPP, AD, SCC, BCC, bullous pemphigoid, dermatitis herpetiformis, chronic prurigo/prurigo nodularis, subacute prurigo, and prurigo pigmentosa. In contrast, there are a number of skin diseases that feature neutrophilic infiltration without itch, such as cellulitis, erysipelas, Sweet syndrome, Beçhet disease, and pyoderma gangrenosum. This may be due to the fact that, in the majority of these diseases, neutrophils infiltrate deeper beyond the epidermis and dermo-epidermal junction; but the clear explanation is still to be determined. Further research is needed to clarify the pathogenetic roles of neutrophils in itch.
G.Y.: designed the paper. T.H.: reviewed the literature and wrote the manuscript. J.D.R., K.M.S., and G.Y.: revised it critically. All authors have read and approved the final manuscript.
Conflict of interest disclosures
G.Y. has been a consultant, advisory board member and supported as a researcher for the following drug companies: Menlo, Trevi, Sienna, Opko, Sanofi, Galderma, Novartis, Pfizer, Eli Lilly, and Sun Pharma. T.H. has received scholarships from the Uehara Memorial Foundation and the Japanese Society of Allergology. The remaining authors declare that they have no financial conflict of interest with regard to the content of this report.
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