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

Abstract

SummaryPyoderma 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)-a, interleukin (IL)-8 and IL-17], metalloproteinases (MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF). Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-a, 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.

Pyoderma gangrenosum: challenges and solutions

“…Furthermore, the increase of elafin, the neutrophil elastase inhibitor, expressed by injured epidermal keratinocytes, and the intensification of the FAS/FASL system, involved in tissue damage and apoptosis, may also contribute to the formation of ulcers in PG, and impairment of tissue remodeling and wound healing. 10,13,14 IL17 produced by Th17 cells, shown to play an important role in IBD and other skin diseases that involve neutrophil recruitment, like psoriasis and acute generalized exanthematous pustulosis, has also been found to be elevated in skin lesions of PG. 12,[14][15][16] Th17 cells seem to be overrepresented in PG lesions together with a low level of regulatory T cells (Treg) and related cytokines, namely IL10.…”

“…8 In PG and other neutrophilic diseases, elevated skin and/or circulating levels of the pro-inflammatory cytokines (IL1β, IL6, TNF-α, IFN-ϒ, G-CSF) [10][11][12] and, particularly, of the potent PMN attracting chemokines, namely IL8/CXCL8 and CXCL1,2,3, along with skin infiltration by T cells, particularly at the edge of the PG ulcer, suggests an active recruitment of PMN to the skin. 10,13 Also, in both PG and SS skin lesions, there is a high expression of MMPs (MMP-2, MMP-9, MMP-10), a family of Zn2+ endopeptidades that are not only major contributors to the breakdown and reconstitution of the extracellular matrix in wound repair, but also influence the production of neutrophilic chemokines in neutrophilic disorders. Furthermore, the increase of elafin, the neutrophil elastase inhibitor, expressed by injured epidermal keratinocytes, and the intensification of the FAS/FASL system, involved in tissue damage and apoptosis, may also contribute to the formation of ulcers in PG, and impairment of tissue remodeling and wound healing.…”

“…8 Additionally, PG lesions are almost always observed in patients with PAPA syndrome, a rare inherited auto-inflammatory syndrome with excessive IL1 production. 13,20 Genetic abnormalities have been found in patients with PG in the context of PAPA, PAPASH (initially described as PASS -pyogenic arthritis, PG, acne, and hidradenitis suppurativa), and PASH (PG, acne, and hidradenitis suppurativa) syndromes in genes that code for an aberrant production of IL1, namely PSTPIP1 gene, 8,21,22 or in its promoters. 20 In cases of PG associated with IBD, genetic abnormalities have occasionally been found concerning loci for IL8RA, and TIMP3 and TRAF31P2 genes, which code respectively for an MMP inhibitor and a protein that interacts with TNF receptor-associated factors, involved in the IL17 immune pathway.…”

Inflammatory Cells, Cytokines and Matrix Metalloproteinases in Amicrobial Pustulosis of the Folds and other Neutrophilic Dermatoses

“…Moreover, we recently demonstrated a marked expression of IL-8 by the cells composing the dermal inflammatory infiltrate in PG, particularly 'l-Iymphocytes and macrophages, with the most intense IL-8 labelling at the wound bed, where there is the predominant neutrophil recruitment and consequent tissue damage (14). In the present study, we found hyperexpression of IL-8 also in APF, but its immunoreactivity was significantly lower than in PG and similar to that seen in Sweet's syndrome.…”

“…Received January 5, 2011 -Accepted April 14,2011 Amicrobial pustulosis of the folds (APF) is a rare cutaneous disease characterized by relapsing sterile pustules frequently associated with autoimmune disorders. Although APF pathophysiology is still undefined, scattered reports suggest involvement of neutrophils.…”