Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases

Authors

  • A. V. Marzano,

    1. Unità Operativa di Dermatologia, Fondazione IRCCS Ca' Granda – Ospedale Maggiore Policlinico, Dipartimento di Anestesiologia, Terapia Intensiva e Scienze Dermatologiche, Università degli Studi di Milano,
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  • M. Cugno,

    Corresponding author
    1. Dipartimento di Medicina Interna, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda – Ospedale Maggiore Policlinico, Milano, Italy
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  • V. Trevisan,

    1. Unità Operativa di Dermatologia, Fondazione IRCCS Ca' Granda – Ospedale Maggiore Policlinico, Dipartimento di Anestesiologia, Terapia Intensiva e Scienze Dermatologiche, Università degli Studi di Milano,
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  • D. Fanoni,

    1. Unità Operativa di Dermatologia, Fondazione IRCCS Ca' Granda – Ospedale Maggiore Policlinico, Dipartimento di Anestesiologia, Terapia Intensiva e Scienze Dermatologiche, Università degli Studi di Milano,
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  • L. Venegoni,

    1. Unità Operativa di Dermatologia, Fondazione IRCCS Ca' Granda – Ospedale Maggiore Policlinico, Dipartimento di Anestesiologia, Terapia Intensiva e Scienze Dermatologiche, Università degli Studi di Milano,
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  • E. Berti,

    1. Unità Operativa di Dermatologia, Fondazione IRCCS Ca' Granda – Ospedale Maggiore Policlinico, Dipartimento di Anestesiologia, Terapia Intensiva e Scienze Dermatologiche, Università degli Studi di Milano,
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  • C. Crosti

    1. Unità Operativa di Dermatologia, Fondazione IRCCS Ca' Granda – Ospedale Maggiore Policlinico, Dipartimento di Anestesiologia, Terapia Intensiva e Scienze Dermatologiche, Università degli Studi di Milano,
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M. Cugno, Department of Internal Medicine, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Via Pace 9 – 20122 Milano, Italy.
E-mail: massimo.cugno@unimi.it

Summary

Pyoderma gangrenosum (PG) is a rare, immune-mediated inflammatory skin disease presenting with painful ulcers having undermined edges. Less commonly, bullous and vegetative variants exist. Histology consists of a neutrophil-rich dermal infiltrate. We characterized immunohistochemically the infiltrate in different variants of PG and in another neutrophilic dermatosis as Sweet's syndrome. We studied 21 patients with PG, eight with Sweet's syndrome and 20 controls, evaluating skin immunoreactivity for inflammatory cell markers (CD3, CD163 and myeloperoxidase), cytokines [tumour necrosis factor (TNF)-α, interleukin (IL)-8 and IL-17], metalloproteinases (MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF). Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-α, IL-8, IL-17, MMP-2, MMP-9 and VEGF were significantly higher in both PG and Sweet's syndrome than in controls (P = 0·0001). Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed more significantly in both ulcerative and bullous PG than in vegetative PG as well as in Sweet's syndrome (P = 0·008–P = 0·0001). In ulcerative PG, the expression of CD3 (panT cell marker) and CD163 (macrophage marker) were significantly higher in wound edge than wound bed (P = 0·0001). In contrast, the neutrophil marker myeloperoxidase was expressed more significantly in wound bed than wound edge (P = 0·0001). Our study identifies PG as a paradigm of neutrophil-mediated inflammation, with proinflammatory cytokines/chemokines and MMPs acting as important effectors for the tissue damage, particularly in ulcerative and bullous PG where damage is stronger. In ulcerative PG, the wound bed is the site of neutrophil-recruitment, whereas in the wound edge activated T lymphocytes and macrophages pave the way to ulcer formation.

Introduction

Pyoderma gangrenosum (PG) is a rare, immune-mediated inflammatory skin disease that starts typically with folliculitis-like pustules, evolving rapidly into painful ulcers of variable size and depth, with undermined violaceous borders. In addition to the classical ulcerative form of PG mentioned above, less common bullous and vegetative variants exist [1–4]. Histopathology of ulcerative PG, albeit not distinctive, is suggestive, showing a dense dermal infiltrate composed mainly of neutrophils in biopsy from an area of ulceration and a mainly lymphocytic infiltrate with thrombosis of vessels and extravasated erythrocytes in biopsy from the border of the ulcer [4]. The pathological changes of bullous PG are characterized by a neutrophilic-rich dermal infiltrate with microabscess formation and subepidermal blister. Vegetative PG demonstrates not only neutrophils, but also lymphocytes and hystiocytes within the inflammatory infiltrate as well as giant cells and granuloma formation. PG may occur in association with a wide variety of conditions, particularly inflammatory bowel disease (IBD), and haematological malignancies, or can be idiopathic.

Concerning the management of PG, systemic treatment with corticosteroids and cyclosporine is considered to be the first-line therapy for this condition [5], but no definite guidelines have been established so far. Recently, biologics, most notably tumour necrosis factor (TNF)-α antagonists such as infliximab, have been employed successfully for refractory PG [2], while in localized forms topical therapy, most notably tacrolimus, may represent a valid therapeutic option [6]. Another immune-mediated dermatosis characterized by an infiltrate of mature neutrophils located typically in the upper dermis is Sweet's syndrome, which presents clinically with pyrexia, elevated neutrophil count and painful erythematous papules and nodules, possibly coalescing into plaques [7]. A bullous form of Sweet's syndrome exists, and some authors believe that the bullous variants of PG and Sweet's syndrome represent points on a continuum of diseases that have dermal neutrophilia in common [8]. Another noteworthy similarity between PG and Sweet's syndrome is represented by the associated conditions, particularly IBD and haematological neoplasms. Conversely, in Sweet's syndrome prompt clinical improvement is usually obtained following the initiation of systemic corticosteroid monotherapy. Although PG and Sweet's syndrome are classified within the spectrum of the so-called neutrophilic dermatoses [4], several physiopathological aspects as well as molecular effectors mediating tissue destruction in both diseases remain largely unknown. With this background we evaluated, by immunohistochemistry, the phenotyping of the inflammatory infiltrate and expression of proinflammatory and multi-functional cytokines, such as tumour necrosis factor (TNF)-α, interleukin (IL)-8 and IL-17, well-known effectors of the tissue damage, such as matrix metalloproteinases (MMP)-2 and -9, and a molecule amplifying the inflammatory network such as vascular endothelial growth factor (VEGF) in both PG and Sweet's syndrome, to clarify their pathophysiologies and to recognize similarities and differences between them.

Patients and methods

Patients

Lesional skin biopsies taken from 21 patients with PG (12 men and nine women; mean age 48 years, range 15–78 years) and eight patients with Sweet's syndrome (three men and five women; mean age 44 years, range 26–60 years) were studied immunohistochemically. Various clinical subtypes of PG were represented, namely ulcerative (11 cases), vegetative (five cases) and bullous (five cases) type. The ‘classic’ papulonodular presentation of Sweet's syndrome was seen in seven of eight patients, while the other patient had a bullous variant. The diagnosis of PG as well as of Sweet's syndrome was established on the basis of clinical and histopathological criteria. Nine patients with PG had various associated conditions, including IBD (four patients with the ulcerative variant and another patient with the vegetative form), immunoglobulin (Ig)A λ myeloma (one patient with the bullous type), IgA monoclonal gammopathy (one patient with the ulcerative variant), Klinefelter's syndrome (one patient with the bullous type) and cystic fibrosis (one patient with the vegetative form); in the other 12 cases PG was idiopathic. Only one patient with papulonodular Sweet's syndrome had an associated chronic B cell lymphatic leukaemia.

Immunohistochemical studies

The biopsies were performed before introduction of systemic treatment for both PG and Sweet's syndrome. In ulcerative PG patients, skin specimens were taken from the undermined edge surrounding the ulcerative lesion to the centre of the ulcer. In both vegetative and bullous patients, as well as in Sweet's syndrome cases, specimens were obtained from lesional skin. The controls were normal skin tissue specimens taken from 20 patients who underwent excision of benign skin tumours The tissue samples were fixed in buffered formalin, dehydrated, embedded in paraffin wax and sectioned; no antigen unmasking pretreatment was needed. After deparaffining and rehydrating, each tissue section was placed on a Dako automated immunostainer (Dako Cytomation, Glostrup, Denmark), and incubated with the specific monoclonal antibody at room temperature for 45 min, and then washed with Tris-buffered saline (TBS), pH 7·6, and incubated in biotinylated goat anti-mouse and anti-rabbit immunoglobulins (Dako REAL™, code K5005) at room temperature for 30 min. After incubation with the secondary antibody and another washing with TBS, pH 7·6, the sections were incubated with streptavidin conjugated to alkaline phosphatase (Dako REAL™, code K5005) at room temperature for 30 min. We used specific monoclonal antibodies to CD3 (polyclonal rabbit; Dako), CD163 (10D6; Novocastra Laboratories Ltd, Newcastle upon Tyne, UK), myeloperoxidase (polyclonal rabbit; Dako), TNF-α (52B83; Monosan, Uden, the Netherlands), VEGF (VG1; Dako), IL-8 (DM/C7; Genzyme Corporation, Cambridge, MA, USA), IL-17 (41802; R&D Systems, Minneapolis, MN, USA), MMP-9 (6-6B, Calbiochem EMD Chemicals, Inc., Gibbstown, NJ, USA) and MMP-2 (Calbiochem EMD Chemicals, Inc). A red chromogen solution was prepared as indicated by the Dako REAL™ datasheet and used as an enzyme substrate, followed by counterstaining with Mayer's haematoxylin. After air-drying, each section was coverslipped using the VectaMount™ mounting medium (Vector Laboratories, Burlingame, CA, USA). A negative control was performed using a pool of mouse immunoglobulins (IgG1, IgG2a, IgG2b and IgM) as primary antibody (negative control; Dako Cytomation). Two independent ‘blinded’ observers evaluated the serial sections. Immunoreactivity was scored according to the number of immunoreactive cells per field (×200): 0 = no immunoreactive cells; 1 = 1–5 cells; 2 = 6–20 cells; 3 = >20 cells.

Statistics

Differences in the immunohistochemical scores were assessed using the Wilcoxon–Mann–Whitney non-parametric test; a P-value of <0·05 was considered to indicate a statistically significant difference.

Results

Phenotyping of the inflammatory infiltrate in PG

The phenotyping of the inflammatory infiltrate showed significant differences among the different variants of PG, i.e. ulcerative, vegetative and bullous (Fig. 1), and between the undermined edge surrounding the skin ulcer and the wound bed in ulcerative PG (Fig. 2). In the latter, an intense expression of both CD3, a T cell marker, and CD163, a macrophage antigen, was detected at the wound edge, where only slight reactivity for the neutrophil marker myeloperoxidase was found. In contrast, at the wound bed, the inflammatory infiltrate was slightly immunostained for CD3 and CD163, with strong expression of myeloperoxidase (Figs 2 and 3). In vegetative PG, an abundant expression of CD163 with only mild staining for both CD3 and myeloperoxidase was evident. Finally, the inflammatory infiltrate of bullous PG was characterized by very strong immunoreactivity for myeloperoxidase and slight expression of both CD3 and CD163 (Figs 1 and 4).

Figure 1.

Immunohistochemical reactivity of inflammatory cell markers (CD3, CD163 and myeloperoxidase), cytokines [tumour necrosis factor (TNF)-α, interleukin (IL)-8 and IL-17], metalloproteinases (MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF) in different variants of pyoderma gangrenosum, i.e. ulcerative (UPG), vegetative (VPG) and bullous (BPG), in classic Sweet's syndrome and in 20 normal controls. Immunoreactivity was scored according to the number of immunoreactive cells per field (×200): 0 = no immunoreactive cells; 1 = 1–5 cells; 2 = 6–20 cells; 3 = >20 cells. The expression of the above-mentioned effector markers was significantly higher in both PG and Sweet's syndrome than in normal controls (P = 0·0001). Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed more significantly in both ulcerative and bullous pyoderma gangrenosum (PG) than in vegetative PG as well as in Sweet's syndrome (P = 0·008–P = 0·0001). In contrast, the macrophage marker CD163 was expressed more significantly in vegetative PG than in the other PG variants as well as in Sweet's syndrome (P = 0·032–P = 0·003). The expression of TNF-α or IL-17 was not significantly different within the PG variants as well as between PG and Sweet's syndrome. VEGF values were also not significantly different in the PG variants and Sweet's syndrome.

Figure 2.

Immunohistochemical reactivity of inflammatory cell markers (CD3, CD163 and myeloperoxidase), cytokines (TNF-α, IL-8 and IL-17), metalloproteinases (MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF) in ulcerative pyoderma gangrenosum at the wound edge and wound bed. Immunoreactivity was scored according to the number of immunoreactive cells per field (×200): 0 = no immunoreactive cells; 1 = 1–5 cells; 2 = 6–20 cells; 3 = >20 cells. The expression of both CD3 (a panT cell marker and CD163 (a macrophage marker) were significantly higher in wound edge than in wound bed (P = 0·0001 for both). In contrast, the neutrophil marker myeloperoxidase was expressed more significantly in the wound bed than in the wound edge (P = 0·0001). Also, the chemokine IL-8 (P = 0·0001) and the matrix metalloproteinases (MMP) 2 (P = 0·009) and 9 (P = 0·001) showed a significantly higher immunoreactivity in the wound bed than in the wound edge. In the wound edge the immunoreactivity for both TNF-α and IL-17 was slightly increased (P = 0·017 and P = 0·028, respectively). VEGF values were not significantly different in the wound edge and bed.

Figure 3.

Immunohistochemical studies of CD3, CD163 and myeloperoxidase in ulcerative pyoderma gangrenosum (PG) (original magnification ×100). An intense expression of both CD3 (panT-cell marker) and CD163 (macrophage antigen) is evident at the wound edge (upper panels), where only slight reactivity for the neutrophil marker myeloperoxidase is seen. In contrast, at the wound bed (lower panels), the inflammatory infiltrate is slightly immunostained for CD3 and CD163, with strong expression of myeloperoxidase.

Figure 4.

Immunohistochemical studies of CD3, CD163 and myeloperoxidase in vegetative pyoderma gangrenosum (PG) (upper panels) and bullous PG (lower panels) (original magnification ×100). In vegetative PG, an abundant expression of CD163 with only mild staining for both CD3 and myeloperoxidase is evident. The inflammatory infiltrate of bullous PG is characterized by very strong immunoreactivity for myeloperoxidase and slight expression of both CD3 and CD163.

Phenotyping of the inflammatory infiltrate in Sweet's syndrome

Phenotyping of the inflammatory infiltrate of classic papulonodular Sweet's syndrome revealed moderate expression of CD3 and a slight expression of both CD163 and myeloperoxidase (Figs 1 and 5). We evaluated a single case of bullous Sweet's syndrome which differed in that a strong expression of myeloperoxidase was seen.

Figure 5.

Immunohistochemical studies of CD3, CD163 and myeloperoxidase in Sweet's syndrome (original magnification ×100). A moderate focal expression of CD3 and a slight expression of both CD163 and myeloperoxidase are evident.

Cytokine expression in PG

In ulcerative PG, an intense immunoreactivity with the monoclonal antibody (mAb) directed against IL-8 was found at the wound bed (Fig. 6); interestingly, the above chemokine was expressed only slightly at the edge of the ulcer. The immunoreactivity for TNF-α and IL-17 was intense, albeit less strong than IL-8; it is of note that the immunostaining was diffuse, with a predominance at the wound edge. In both vegetative and bullous PG, reactivity that was moderate for TNF-α and mild for IL-17, respectively, was seen, both cytokines showing a diffuse expression pattern. In contrast, IL-8 expression results were markedly stronger in bullous PG than in vegetative PG.

Figure 6.

Immunohistochemical studies of interleukin (IL)-8 and vascular endothelial growth factor (VEGF) in ulcerative pyoderma gangrenosum (PG) (original magnification ×100). The immnoreactivity of IL-8 is strong at the wound bed. VEGF is moderate and diffuse.

Cytokine expression in Sweet's syndrome

In classic Sweet's syndrome, moderate expression of TNF-α and slight expression of both IL-8 and IL-17 were detected. Thus, the cytokine pattern of classic Sweet's syndrome appeared to be strictly similar to that of vegetative PG. In contrast, in bullous Sweet's syndrome the cytokine expression pattern mimicked closely that of bullous PG, particularly for strong IL-8 expression.

MMPS expression in PG

In ulcerative PG, MMP-9 was expressed strongly at the wound bed with the same pattern of myeloperoxidase, and to a lower extent in the wound edge. The immunoreactivity for MMP-2 appeared less intense than MMP-9, but showing the same expression pattern. A strong MMP-9 expression and a moderate MMP-2 expression were observed in bullous PG, whereas only slight immunostaining for both MMP-2 and MMP-9 was detected in vegetative PG (Figs 1 and 7).

Figure 7.

Immunohistochemical studies of metalloproteinase (MMP)-9 in ulcerative pyoderma gangrenosum (PG) (wound bed), vegetative PG and bullous PG (original magnification ×100). A strong MMP-9 expression is observed in both ulcerative and bullous PG, whereas only slight immunostaining is seen in vegetative PG.

MMPS expression in Sweet's syndrome

In classic Sweet's syndrome, the reactivity of both MMP-2 and MMP-9 was low, similar to vegetative PG (Figs 1 and 8). In contrast, the single case of bullous Sweet's syndrome was characterized by high MMP-9 expression, as in bullous PG.

Figure 8.

Immunohistochemical studies of metalloproteinase (MMP)-2 and MMP-9 in classic Sweet's syndrome (original magnification ×100). The reactivity of both MMP-2 and MMP-9 is low.

VEGF expression in PG

Moderate expression of VEGF was evident in both bullous and ulcerative PG; in the latter, there was no clear difference in VEGF expression between edge and bed of the ulcer (Fig. 6). VEGF expression was less intense in the vegetative variant.

VEGF expression in Sweet's syndrome

The VEGF expression in classic Sweet's syndrome has mimicked that seen in vegetative PG, while VEGF expression in the bullous form has resembled that found in the bullous variant of PG.

Discussion

To the best of our knowledge, accurate phenotyping of the inflammatory infiltrate had never been performed, either in PG or in Sweet's syndrome. Here, we demonstrated in both disorders a polymorphic infiltrate consisting of T lymphocytes, macrophages and neutrophils. Interestingly, there was a clear-cut difference between classic ulcerative PG and classic papulonodular Sweet's syndrome, because the neutrophil marker myeloperoxidase was expressed strongly only in the wound bed of PG. Thus, although the neutrophil plays a pivotal role in the pathogenesis of both diseases, it seems to be the major effector cell in a condition such as the ulcerative variant of PG that is characterized by the strongest tissue damage within the spectrum of neutrophilic dermatoses. It is of note that the infiltrate at the undermined border surrounding the ulcer was composed mainly of CD3+ T lymphocytes and CD163+ macrophages, which precede the transendothelial migration of neutrophils, and resembles that of the vegetative form of PG. These last findings are in agreement with the clinical observation that the vegetative PG lesions may be the evolution of an ulcerative PG lesion, when macrophages in particular become predominant following progressive reduction of neutrophilic recruitment. An intense expression of myeloperoxidase was found in both bullous PG and bullous Sweet's syndrome, supporting the view that they may be regarded as overlap conditions.

Interesting results were obtained in our study evaluating the expression of a panel of classic and recently identified cytokines. Overproduction of TNF-α, as confirmed by the staining with the anti-TNF-α moAb seen in all the PG variants, plays an important role in the development of the inflammatory process in this disorder, providing the rationale for the use of anti-TNF-α therapy [9]. Moderate TNF-α expression was noted in both classic and bullous Sweet's syndrome, suggesting that this cytokine may also contribute to amplification of the inflammatory network in other neutrophilic dermatoses. In fact, TNF-α is a powerful proinflammatory cytokine that acts as a key regulator of other proinflammatory cytokines, including IL-1 β, IL-6 and IL-8, the latter being a potent chemotactic polypeptide for neutrophils [10]. High levels of IL-8 are immunohistochemically detectable in dermal fibroblasts from ulcers of patients with PG [11]. Moreover, fibroblasts from the ulcer of PG produce high levels of IL-8 in vitro[12], and serum levels of this chemokine have been shown to be increased in PG [13] as well as in ulcerative colitis [14]. According to these findings, our study revealed marked expression of IL-8 by activated fibroblasts and endothelial cells, as well as by the cells composing the dermal inflammatory infiltrate in PG, particularly T lymphocytes and macrophages. Our observations highlight strongly the involvement of IL-8 in the pathogenesis of PG. It is of interest that the most intense IL-8 labelling was detected at the wound bed of ulcerative PG, where there is predominant neutrophilic recruitment and consequent tissue damage, and IL-8 immunoreactivity was significantly different compared to both vegetative PG and classic Sweet's syndrome (P = 0·022–P = 0·002). Although these results support the relationship between PG and Sweet's syndrome within the spectrum of neutrophilic dermatoses, they emphasize that ulcerative PG usually follows a more aggressive clinical behaviour and often requires a stronger immunosuppressive treatment, compared to both its vegetative variant and classic Sweet's syndrome. Conversely, another important parameter that influences the prognosis of PG is represented by the extension of cutaneous lesions. In our study, IL-17 proved to be expressed both in PG and, albeit less intensely, in Sweet's syndrome, suggesting a potential role for this cytokine in the pathophysiology of the whole spectrum of neutrophilic dermatoses, as recognized recently in psoriasis [15]. IL-17 is a proinflammatory cytokine produced primarily by a new T helper cell subset termed ‘Th17’[16] that exerts its effects through the recruitment of monocytes and neutrophils by increasing the local production of chemokines, most notably IL-8 [17]. Moreover, it facilitates T lymphocyte infiltration and activation by stimulating the expression of intercellular adhesion molecule-1 [18] and amplifies the immune response by synergizing with various other cytokines, in particular with TNF-α[19], and inducing the production of MMPs [20]. MMPs represent a family of Zn2+-containing endopeptidades that are major contributors in the breakdown and reconstitution of the extracellular matrix (ECM) in both physiological processes, such as tissue remodelling during development and wound repair, and in pathological conditions, in particular in immune-mediated diseases [21]. Gelatinases are a subgroup of MMPs composed of two members: MMP-2 (gelatinase A), a 72 KDa proteinase produced primarily by stromal cells, and MMP-9 (gelatinase B), a 92 kDa proteinase synthesized mainly by inflammatory cells, particularly neutrophils, which specifically degrade most components of the ECM [22]. Interestingly, the expression of MMP-2 and more strongly of MMP-9 at both the protein and mRNA levels has been found to be enhanced in intestinal inflammatory bowel disease tissue, with the highest levels in inflamed areas and especially in the acute phase [23]. An improper activity of MMP-9 is thought to cause the destruction of tissue via the degradation of components of the ECM and, in addition, to influence the production of neutrophilic chemokines, promoting neutrophil transendothelial migration into the site of inflammatory process [24]. Thus, the MMP-9 overexpression in the inflammatory infiltrate of classic ulcerative PG appears to be the most noteworthy finding of our study, suggesting that this proteinase and to a lesser degree MMP-2 may be relevantly involved in inducing both tissue damage and repair in this disease, as hypothesized for inflammatory bowel diseases [23]. MMP-9 was expressed strongly at the wound bed and its immunoreactivity pattern resembled that of myeloperoxidase, indicating that the neutrophil is conceivably the major source of this proteinase in ulcerative PG lesional skin. MMP-9 and MMP-2 were expressed less significantly in both vegetative PG and classic Sweet's syndrome than in ulcerative PG (P = 0·022–P = 0·002). These findings are in agreement with the less aggressive clinical behaviour of both vegetative PG and classic Sweet's syndrome.

Finally, VEGF was overexpressed in both PG and Sweet's syndrome, although with varying degrees of reactivity. VEGF, identified originally as an endothelial cell specific growth factor stimulating angiogenesis, plays a multi-functional role where the effect of increasing vascular permeability is crucial, leading to enhancement of leucocyte recruitment into the site of inflammation [25,26].

In conclusion, the present study stresses the crucial role of neutrophils in the pathophysiology of PG, with proinflammatory cytokines, chemokines and MMPs acting as important effectors responsible for neutrophil-mediated tissue damage, particularly in ulcerative and bullous PG and less in vegetative PG and Sweet's syndrome. Thus, our data highlight that classic PG may be regarded as the most aggressive form within the spectrum of neutrophilic dermatoses. In ulcerative PG, the wound bed is the site of neutrophil-recruitment and tissue damage, whereas in the wound edge activated T lymphocytes and macrophages pave the way to ulcer formation.

Disclosure

None.

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