Inflammatory Events Are Involved in Acne Lesion Initiation

Abstract

The earliest subclinical acne "lesion" is a microcomedone, of which hyperproliferation of the follicular epithelium is a characteristic feature. Inflammatory cells have been observed at the periphery of these "lesions". This study investigated whether inflammatory events occur pre or post hyperproliferative changes. Cellular, vascular, and proliferative markers were examined by immunohistochemical techniques on biopsies of clinically normal follicles from uninvolved skin and early inflamed lesions from acne patients. Control follicles were obtained from non-acne subjects. Follicles from uninvolved skin exhibited no microcomedonal features. Proliferation in the epithelium was comparable to controls and was significantly lower than in inflamed lesions. Numbers of CD3+, CD4+ T cells were elevated in the perifollicular and papillary dermis although levels were not equivalent to those in papules. The number of macrophages was also greatly increased and similar to those in papules. There were no changes in blood vessel numbers or vascular intercellular adhesion molecule 1 expression but E-selectin expression was increased to levels found in papules and vascular adhesion molecule 1 levels were upregulated. Levels of the pro-inflammatory cytokine interleukin-1 were also upregulated perifollicularly. Moreover, aberrant integrin expression was demonstrated in the epidermis around these uninvolved follicles and inflamed lesions whereas the basement membrane was still intact. These results provide novel evidence for vascular endothelial cell activation and involvement of inflammatory responses in the very earliest stages of acne lesion development.

Role of FGFR2-signaling in the pathogenesis of acne

“…149 Immunohistochemical studies of earliest subclinical acne lesions demonstrated an increase of IL-1α labelling in all layers of interfollicular and perifollicular epidermis and down the follicle wall of uninvolved skin of acne patients compared to controls. 150 Down the follicular wall only labelling in the infrainfundibular basal cells increased, whereas labelling in the suprabasal layers of the infrainfundibulum and all layers of the acroinfundibulum did not differ in intensity in uninvolved skin of acne patients and early inflamed lesions. 150 Within the dermis IL1-α labelling presented a discrete cellassociated immunoreactivity with the majority of positive cells located perifollicularly, whereas in normal skin only a small number of dermal cells expressed IL-1α.…”

“…159 It is most likely that increased IL-1α activity has initiated the upregulation of vascular adhesion molecules, ICAM-1, E-selectin and VCAM-1 and the cellular migration of CD4 + -T-cells and macrophages found in uninvolved and early inflammatory lesions of acne patients. 150 It is conceivable that androgen-dependent FGFR2-mediated release of IL-1α by infrainfundibular keratinocytes is the primary stimulus leading to comedogenesis, a state of secretory keratinocyte activation inducing the perifollicular infiltration by T-cells and macrophages. A further link between IL-1α and initiation of the immune response is the fact that, activated IL-1 receptor associated kinases (IRAKs) are critically involved in the IL-1 receptor/Toll-like receptor-mediated signal transduction processes that regulate cellular innate and adaptive immune responses.…”

An update on the role of the sebaceous gland in the pathogenesis of acne

“…65 MC-1R expression has been shown to be upregulated by proinflammatory signals. 66,67 As proinflammatory cytokines are upregulated in acne lesions, 68 sebocytes may respond to these signals with increased MC-1R expression, thereby generating a negative feedback mechanism for α-MSH which exerts direct anti-inflammatory actions, i.e., inhibition of IL-1-mediated IL-8 secretion. 64,65 Cannabinoid receptors (CR), which mediate the psychopharmacological action of marijuana have been not only localised in the central and peripheral nervous system but also in human skin.…”

“…Recent studies support the latter hypothesis by demonstrating that an increase in IL-1 activity occurs before the hyperproliferation around uninvolved follicles and this triggers the activation of the keratinocytes. 68,75 Expression profiling of acne-involved and uninvolved skin from cells and of E-selectin by perisebaceous venules. Facial skin from acne patients is characterised by rich innervation, by increased numbers of substance P-containing nerves and mast cells, and by strong expression of neutral endopeptidase in sebaceous glands and E-selectin in venules around sebaceous glands, compared with normal skin.…”

“…It has proliferation and may play a profound role in the transformation of a normal follicle into an acne lesion. 68 Inflammation is further characterised by action of active lipid mediators, such as leucotrienes (LT), prostaglandins (PG) and 15-hydroxyeicosatetraenoic acids (15-HETE). These molecules are synthesised from arachidonic acid (AA) or linolenic acid by the enzymes lipoxygenase (LOX) and cyclooxygenase (COX), respectively.…”