Retinoids affect the inflammatory pathways of acne lesion development indirectly via their ability to normalize hyperkeratinization. However, they also exert direct immunomodulatory effects by competing with transcription factors like AP-1.
However, in trying to distill the available information into a more basic view, Neal D. Bhatia, M.D., assistant clinical professor of dermatology, University of Wisconsin Medical School, Madison, suggests there are three key points to remember regarding promoters and inhibitors of the inflammatory pathways:
IL-1A CENTER OF CYTOKINE TEAM Dr. Bhatia says the finding of high levels of the Th1 type cytokines IL-1a, IL-12 and TNF-alpha in the skin of acne patients indicates that in addition to involving humoral immunity, acne pathogenesis and cellular immunity go hand in hand.
In an analogy comparing the effects of the various cytokines to the roles of players on a football team, Dr. Bhatia explains that IL-1a would be the center because it initiates the entire play cascade and signals the T-helper cells (the quarterback) to secrete IL-2. However, this happens through multiple pathways.
"IL-1a may be considered the king of comedogenesis because it promotes keratinocyte hyperproliferation, but it also increases follicular wall permeability that enables access of the ruptured follicular contents into the dermis. In addition, IL-1a induces the release of other pro-inflammatory cytokines and chemoattractants that perpetuate the inflammatory cascade and further disrupt follicular wall integrity. Inflammatory lesion development occurs as the end result," he tells Dermatology Times.
P. ACNES - ENEMY NO. 1 Dr. Bhatia says that P. acnes represents "enemy No. 1" in acne pathogenesis, and it uses multiple tactics to promote acne development and scarring.
P. acnes stimulates activity of the pattern recognition receptor (PRP) and binds to toll-like receptor-2 (TLR-2) on macrophages and keratinocytes to cause release of IL-1a and other pro-inflammatory cytokines, and recently, it has been reported to stimulate the intracellular PRP, nucleotide oligomerization domain (NOD), which initiates inflammation via a different pathway. Furthermore, P. acnes activates the complement cascade, produces free fatty acids via digestion and metabolism of sebum, and releases hydrolytic enzymes that promote release of follicular contents. In addition, P. acnes plays a role in the development of scarring secondary to its activity in supporting release of Th1-type cytokines.
"As enemy No. 1, P. acnes is also a very clever and formidable foe. Because it is an anaerobe, it is able to evade intracellular mechanisms of pathogen-killing, and by digesting sebum, it creates its own fuel," Dr. Bhatia, who is also in private practice in Milwaukee, Wis., says.
RETINOIDS TO THE RESCUE By virtue of their multimodal mechanisms, retinoids are versatile warriors in combating acne.
Retinoids effect the inflammatory pathways of acne lesion development indirectly via their ability to normalize hyperkeratinization. However, they also exert direct immunomodulatory effects by competing with transcription factors like AP-1.
"Retinoids inhibit monocyte expression of TLR-2, thus mitigating the ability of P. acnes to initiate the inflammatory cascade mediated by that receptor. In addition, they bind to nuclear receptors (retinoid acid receptor and retinoid X receptor) that modulate the expression of genes and other transcription factors regulating synthesis and release of proinflammatory cytokines, chemoattractants and collagen-degrading enzymes," Dr. Bhatia explains.