Microcomedones in non‐lesional acne prone skin New orientations on comedogenesis and its prevention

Abstract

Background In non‐lesional skin of acne patients, cyanoacrylate skin surface stripping can harvest a structure called microcomedone (MC) which is the earliest phase of comedogenesis; the root of any subsequent clinical lesion and a target for the prevention of acne relapses. More information is needed on the putative biochemical contributors (biomarkers) of comedogenesis expressed in MC. Methods Proteins expressed in MC were screened by proteomics, immunohistochemistry and Western blotting. The in vitro effects of a comedolytic Silybum marianum fruit extract (SMFE) were studied in sebocyte cultures by RNA‐Seq and modulation of CYP1A1 by qPCR and enzymatic activity. MC severity was correlated to lesions counts and keratin expression during 48 weeks in 23 acne patients using a topical comedolytic formulation containing SMFE. Results Two infundibular keratins, K75 and K79, co‐localized in MC with the sebocyte progenitor cell marker LRIG1 and were used as a biomarker of comedogenesis for the follow‐up of patients. In cultured sebocytes exposed to SMFE (i) transcriptomic analysis showed an up‐regulation by a factor of 15 of RNA coding for K75 and (ii) the gene expression and catalytic activity of CYP1A1 under exposure to dioxin was decreased. In the acne patients using SMFE, the MC index in non‐lesional skin decreased over time and remained until the 48th week, significantly lower than that of the first week. There was a high correlation between the decrease of MC index and the decrease and stability of the clinical lesions counts over time. Importantly, a low MC index status was found to be associated with a significant higher K75 expression in microcomedones. Discussion These observations provide new orientations on the mechanism of comedogenesis and its prevention. Maintaining a low MC status in non‐lesional skin is a sound target for the prevention of acne relapse and a good sentinel of acne remissions.

Recent advances in understanding and managing acne

“…However, keratin expression in the hair cycle in acne lesions has not been studied. A low microcomedo index in acne is associated with significantly higher K75 expression 19 . K75 is expressed in the companion layer between the inner (Henle) layer and outer root sheaths in the lower portion of normal hair follicles 20 .…”

“…Therefore, the hair cycle in acne with microcomedones is directed towards the follicular infundibulum and sebaceous duct instead of the lower portion of hair follicles that comprise companion layers. In addition, K79 is downregulated in comedonal acne lesions 21 and is expressed in companion layers in normal anagen hair follicles 19 . Considering homeostasis in hair cycles in acne, progenitor cells in the junctional zone might differentiate not towards the outer root sheath of hair follicles below the sebaceous duct but towards the infundibulum and sebaceous duct cells in acne.…”

Hidradenitis suppurativa is an autoinflammatory keratinization disease: A review of the clinical, histologic, and molecular evidence

“… 9 , 10 , 11 Comedones are present in flexural and nonflexural inflamed and scarred tissues, as well as noninflamed tissues. 9 , 10 , 11 Subclinical inflammation (observed in hidradenitis suppurativa) 12 , 13 precedes comedogenesis in acne-prone skin, 14 , 15 , 16 , 17 , 18 , 19 , 20 involving keratinocyte-derived proinflammatory mediators (lipoteichoic acid, CCL20, and interleukin [IL] 1α). 18 , 19 , 20 , 21 , 22 , 23 , 24 Ex vivo studies of the follicular infundibum 25 isolated in vitro are able to recapitulate the formation of comedones with addition of IL-1α and prevent formation with the addition of IL-1 receptor antagonist.…”

“… 9 , 10 , 11 Subclinical inflammation (observed in hidradenitis suppurativa) 12 , 13 precedes comedogenesis in acne-prone skin, 14 , 15 , 16 , 17 , 18 , 19 , 20 involving keratinocyte-derived proinflammatory mediators (lipoteichoic acid, CCL20, and interleukin [IL] 1α). 18 , 19 , 20 , 21 , 22 , 23 , 24 Ex vivo studies of the follicular infundibum 25 isolated in vitro are able to recapitulate the formation of comedones with addition of IL-1α and prevent formation with the addition of IL-1 receptor antagonist. 25 It is acknowledged that the in vitro studies performed are based on highly sebaceous follicular units that have distinct differences from apocrine-bearing skin 26 ; however, the similarities in immunologic milieu between sebaceous and apocrine skin in T-helper cell 17–associated mediators 7 , 26 (central to inflammation in hidradenitis suppurativa) 26 raises the possibility that these mechanisms are shared.…”

Dermato‐venereology in the year of coronavirus – Hot topics in research and patient care

“…The role of certain keratins as keratin 79 was studied in the formation of microcomedone which then contribute to comedogenesis in general. In a patient with dioxin poisoning, keratin 79 gene was highly repressed in the skin 14 …”