Researchers reconsider acne development process

Hershey, Pa. - There may be different mechanisms by which Propionibacterium acnes (P. acnes) induce acne vulgaris lesions, recent data indicates. This insight is fueling a re-evaluation of the development process of this common dermatologic condition.

The pathogenesis of acne is multifactorial and includes follicular hyperkeratinization, P. acnes proliferation, sebum production and inflammation. Although P. acnes was long considered to further inflame the skin following the establishment of acne lesions, new research in this field indicates that certain strains of the P. acnes bacteria may have a more direct role in the genesis of acne lesions.

“New insights in the innate immune responses in acne and about the role of various cytokines have broadened our base in the understanding of the pathogenesis of the disease, and may lead to the development of more effective and targeted acne treatments in the future,” says Diane M. Thiboutot, M.D., professor of dermatology, vice-chair for research for dermatology, director of clinical and transitional science research education, Penn State Hershey Dermatology, Hershey, Pa.

Next: The pathogenesis paper trail

Acne pathogenesis

Previous research on the pathogenesis of acne found that CD4+ lymphocytes and interleukin-1 (IL-1) activity were increased in uninvolved areas of acne-prone skin prior to the hyperproliferative changes in the follicle, suggesting that inflammation may precede hyperkeratinization in microcomedone formation (Jeremy A HT, Holland DB, Roberts SG, et al. J Invest Dermatol. 2003;121(1):20-27).

Another previous study looking at the potential involvement of IL-1 in comedogenesis used human hair follicles incubated with IL-1 alpha in vitro and found that IL-1 induced hyperkeratinization within the follicles, very similar to what is seen in comedone formation (Guy R, Green MR, Kealey T. J Invest Dermatol. 1996;106(1):176-182).

According to Dr. Thiboutot, more recent studies performed in the elucidation of the pathogenesis of acne have further investigated the role of IL-1 in comedogenesis, with special focus on the role of inflammasomes.

“The inflammasome is a structure consisting of a series of proteins that work together within the cytoplasm and very similar to toll-like receptors, their task is to recognize foreign pathogen-derived factors as well as other molecules that signal cellular danger,” Dr. Thiboutot says.

Next: The path to inflammation

Production of active IL-1 beta

According to Dr. Thiboutot, the inflammasome is basically comprised of a nod-like receptor protein, caspase-1 and a linker protein. When the pathogen-derived factor (or danger signal) interacts with the inflammasome, it activates caspase-1, which in turn results in the production of active interleukin-1 beta, a cytokine that is very active in initiating inflammation.

One recent in vivo study isolated neutrophils from blood donors and found that P. acnes was capable of strongly activating the inflammasome of human peripheral neutrophils, resulting in the production of active interleukin-1 beta (Sahdo B, Särndahl E, Elgh F, Söderquist B. APMIS. 2012;121(7):652-653).

Another study performed by Qin and colleagues found that P. acnes can activate inflammasomes in human monocytes via the nod-like receptor protein NLRP3 (Qin M, Pirouz A, Kim M-H, et al. J Invest Dermatol. 2013 Oct 24), further supporting a role for the inflammasome activation as being important in the pathogenesis of acne lesions. These findings were soon after corroborated by Kistowska et al in a parallel study in which researchers also found that the P. acnes bacteria can activate inflammasomes via the NLRP3 protein, leading to the production of active capsase-1.

“The Kistowska group took their findings a step further and suggested a mechanism of action, suggested that P. acnes needed to be phagocytized by the cells in order to activate the inflammasome. This is process is associated with the damage to lysosomes and the generation of reactive oxygen species,” Dr. Thiboutot says.

Looking forward, Dr. Thiboutot says the next step would be to examine the mechanisms by which P. acnes activates the innate immune response within the unique microenvironments that arise during acne lesion development and to examine the respective roles of IL-1 alpha and IL-1 beta in this process.

These new findings point to one of the many potential mechanisms by which P. acnes induces inflammation in acne, according to Dr. Thiboutot. They further raise the question, however, about where in the skin, how, and at what time in the pathogenesis of acne is P. acnes having its proinflammatory effect.

“We are learning a lot more about innate immune responses in acne, about the role of various cytokines,” Dr. Thiboutot says, “and one of our challenges moving forward is to try to assess the relative importance of the various cytokines involved in acne, with the thought towards potential new treatments that may address those that seem to be having the largest effect in inducing inflammation.”

Disclosures: Dr. Thiboutot reports no relevant financial interests.

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