Acne vulgaris is a chronic inflammatory disease of the pilosebaceous units characterized by the formation of comedones, erythrematous papules and pustules, less frequently by nodules or pseudocyts 1. It is a pleomorphic disorder with multifactorial pathogenesis 2. Acne has a significant economic and social impact as well as a negative effect on self-image and outlook, especially during the emotionally critical period of adolescence 3. Propionibacterium acnes (P. acnes), an anaerobic pathogen plays an important role in the pathogenesis by triggering the proinflammatory mediators 45 through activation of Toll-like receptors 2 (TLR2) 678. Among these mediators, IL-8 originally identified as neutrophil-activating peptide-1 9, along with P. acnes induce chemotactic factors that play a role in attracting neutrophils to the pilosebaceous unit (6, 7, 8). The production of IL-8 by P. acnes is through activation of the NF-kappa B 10. Gene array expression profiling in acne lesions reveals marked upregulation of genes, including IL-8, involved in inflammation and matrix remodelling 11.

To our knowledge, no reports evaluated the IL-8 IHC expression in skin biopsies of inflammatory acne. Therefore, this study was conducted to assess this expression and to correlate it with disease severity and histological changes in an attempt to understand the disease pathogenesis. The elucidation of this role may highlight the potential role of IL-8 in therapeutic targets in inflammatory acne.

Sixty two percent of the patients were adolescents. Most of patients were females (82.7%) and 79.3% had positive family history of IAV. Almost half (51.7%) of the patients had a disease duration less than 1 year. The exposure to comedogenic agents was positive in 41.4% and history of medications known to cause acne was seen in 34.5%. The demographic characteristics of the patients are summarized in table 1.

IHC expression of IL8 was homogenous and confined to the cytoplasm of the cells. It was identified in all IAV patients with variable expressions in the epidermis and dermis ranging from mild to strong. In the epidermis, all keratinocytes were stained. In the dermis the expression was identified in the pilosebaceous units, inflammatory cells and endothelial cells. In the control group only two cases showed mild epidermal expression, while no staining was observed in the remaining cases (figure 1).

Strong association has been found between the extent of epidermal hyperplasia and hyperkeratosis and the epidermal IHC expression of IL-8 (p < 0.001). In addition, the dermal expression significantly paralleled the extent of inflammatory infiltrate (p < 0.001). Moreover, strong association has been found between the extent of dermal expression and the dermal blood vessels (p < 0.001). Furthermore, significant association has been identified between increased dermal IL-8 IHC expression and the progressive disease course (p = 0.02) but not with the duration of the disease. Table 2 illustrates these associations.

Excessive sebum production secondary to sebaceous gland hyperplasia is the first abnormality to occur in IAV 13. Subsequent hyperkeratinization of the hair follicle prevents normal shedding of the follicular keratinocytes, obstructing the follicle forming an inapparent microcomedo. Lipids and cellular debris accumulate within the blocked follicle 14. This microenvironment encourages colonization of P. acne, which provokes an immune response through the production of numerous inflammatory mediators. Inflammation is further enhanced by follicular rupture and subsequent leakage of lipids, bacteria and fatty acids into the dermis.

Data from this study points out to altered immunoreactivity of IL-8 in the lesional skin of acne patients. This was highlighted by the increased expression in IAV skin biopsies compared to normal ones. Increased immunoreactivity was significantly associated with epidermal hyperplasia, follicular hyperkeratosis. In addition, the more pronounced IL-8 expression of the endothelial cells and neutrophilic infiltrate correlated with the extent of dermal inflammatory response and dermal angiogenesis. This expression is concordant with previous studies showing that IL-8 is released by a variety of cell types including monocytes, macrophages, T lymphocytes, fibroblasts, endothelial cells and keratinocytes in response to inflammatory stimulus 41516. Epidermal hyperplasia and follicular hyperkeratosis secondary to IL-8 production have been noted in psoriatic skin 17. Early studies on IL-8 point out to its inflammatory nature as a chemokine that attracts and degranulates neutrophils 1819. This degranulation release potential key regulators of cell signalling during inflammation such as serine proteases, cathepsin G, leucocyte elastase and proteinase at sites of inflammation, triggering IL-8 and subsequently activate different IL-8 receptors 20.

Contrary to other studies 1421, IL-8 was mildly expressed in normal keratinocytes in non lesional biopsies in two cases while it was absent in the rest. This may be related to the antibody clone used in the present study. In fact, the pattern of staining was different depending on the clone used in the study of Sticherling et al 15, where suprabasal keratinocytes were staining with 52E8 and all keratinocytes were reactive with 46E5. However, the mild or lack of expression of IL-8 in normal keratinocytes in the present work points to its role in mediating and participating to the inflammatory response in IAV cases.

It has been suggested that local changes in the peripheral blood vessels at the dermal papilla or in the interfollicular region may play a role in evolution of IAV because blood vessels can deliver proinflammatory cytokines that modulated a range of inflammatory and proliferative processes 16. IL-8 may be a potential endothelial cell growth and survival factor, interacting through its receptors expressed by endothelial cells. The mechanism of IL-8 regulation of angiogenesis may be in part due to enhanced proliferation and survival of endothelial cells by differential expression of antiapoptosis genes and in part by activation of matrix metalloproteinases 2 and 9 16. This point is supported in the present study by an increase in endothelial cells IHC expression of IL-8 and increased dermal blood vessels in the skin biopsies of IAV patients.

We were able to demonstrate the altered immunoreactivity of IL-8 in IAV compared to normal non lesional skin. An important feature of this study is the strong association between IL-8 IHC expression of endothelial cells and dermal inflammatory response and dermal angiogenesis. Targeted therapy to block IL-8 production may hold promise in limiting the deleterious effects of IL-8-mediated inflammatory response and angiogenesis.

IAV: inflammatory acne vulgris, IHC immunohistochemisty, IL-8: interleukin 8, P. acnes: propionibacterium acnes

The author(s) declare that they have no competing interests.

HA carried out the pathological and IHC evaluation and interpretation, participated in drafting and wrote the final manuscript; NS a post graduate student, conducted the data collection and participated in drafting the manuscript. RM participated in drafting the manuscript and MA participated in the design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.