MMP8 Is Increased in Lesions and Blood of Acne Inversa Patients: A Potential Link to Skin Destruction and Metabolic Alterations

Abstract

Acne inversa (AI; also designated as hidradenitis suppurativa) is a chronic inflammatory disease with still unknown pathogenesis that affects the intertriginous skin of perianal, inguinal, and axillary sites. It leads to painful nodules, abscesses, and fistulas with malodorous secretion and is frequently associated with metabolic alterations. Here, we demonstrate that one of the most highly upregulated molecules in AI lesions is matrix metalloproteinase 8 (MMP8), an enzyme specialized in the degradation of extracellular matrix components and the HDL component apolipoprotein A-I. Granulocytes, which were present in AI lesions, secreted high amounts of MMP8 especially after TNF-α stimulation. Furthermore, activated fibroblasts but not keratinocytes were found to express MMP8. The high lesional MMP8 levels were accompanied by elevated blood levels that positively correlated with TNF-α blood levels and disease severity assessed by Sartorius score, especially with the number of regions with inflammatory nodules/abscesses and fistulas. Additionally, we found a negative correlation between blood MMP8 and HDL-cholesterol levels, suggesting a contributory role of MMP8 in metabolic alterations in AI. In summary, we demonstrate elevated MMP8 levels in AI lesions, suggest their role in skin destruction and metabolic alterations, and recommend the use of MMP8 as blood biomarker for AI disease activity assessment.

Figure 1

MMP8 expression is elevated in lesional skin of AI patients. (a) Picture of affected gluteal skin of a 53-year-old patient suffering from AI with inflammatory lesions and fistulas. (b) MMP8 expression was analyzed in biopsies from skin of 8 healthy control donors and the lesional skin of 10 AI and 10 psoriasis patients by RT-qPCR. Mean data ± SEM are shown. Significance of differences was analyzed using the Mann-Whitney U test (two-tailed; ^∗∗ P < 0.01).

Figure 2

TNF-α stimulates the release of MMP8 from neutrophilic granulocytes. (a) Biopsies from AI lesions were analyzed by IHC. Staining of myeloperoxidase, an enzyme abundantly expressed in neutrophilic granulocytes, in skin sections counterstained with hematoxylin is shown. Scale bar = 25 μm. (b) Human blood cultures were stimulated with the indicated AI-relevant cytokines or were left unstimulated (control) for 4 h. MMP8 concentrations in cell-free supernatants were quantified by ELISA and demonstrated as percent of control. Data from 5 experiments are shown (mean ± SEM). Significance of differences between control versus stimulation groups was analyzed using the Wilcoxon matched-pairs signed-rank test (two-tailed; ^∗ P < 0.05).

Figure 3

Activated fibroblasts but not keratinocytes express MMP8. Primary human dermal fibroblasts (a) and keratinocytes (b) were treated with AI-relevant cytokines as indicated or were left unstimulated (control). Expression was analyzed by RT-qPCR. Data from 3 experiments are shown (mean ± SEM).

Figure 4

MMP8 levels are markedly increased in the blood of AI patients. MMP8 and TIMP-4 blood plasma levels of 20 healthy control donors and 21 AI patients were analyzed by ELISA. Mean data ± SEM are shown. Significance of differences was analyzed using the Mann-Whitney U test (two-tailed; ^∗∗ P < 0.01).

Figure 5

MMP8 blood levels correlate with metabolic alterations in AI patients. Concentrations of MMP8, TNF-α, HDL-cholesterol, triglycerides (TG), and resistin were quantified in blood from 21 AI patients. Data were subjected to Spearman's rank correlation analysis. r _S (Spearman's rank correlation coefficient) is indicated (^∗ P < 0.05, ^∗∗ P < 0.01, and ^∗∗∗ P < 0.001).