Advances in the Understanding of the Pathogenesis of Inflammatory Acne

The paradigm shift regarding comedogenesis has initiated a reexamination of the involvement of P. acnes in the pathogenesis of AV. Although considerable evidence delineates the role of P. acnes in AV, the exact mechanisms by which it contributes to AV are currently in the process of being reevaluated. Studies have shown that P. acnes activates cytokine responses via toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns on microorganisms and elicit immune responses.

In 2002, Kim et al established an association between P. acnes and TLR-2.¹¹ In that study, the investigators found that macrophages presenting TLR-2 were present in the acne lesions, around pilosebaceous follicles, and they increased during the evolution of the disease. In fact, P. acnes was able to induce nuclear factor-κB (NF-κB) activation from transfecting of TLR-2 into a non-responsive cell line. Moreover, in monocytes, P. acnes induced IL-12 and IL-8 protein production that was inhibited by anti-TLR-2 blocking antibodies. In a murine model, P. acnes initiated IL-12 p40 promoter activity via TLR-2, and IL-6 was elicited too. Kim et al felt that their data suggested that P. acnes triggers inflammatory cytokine responses in AV by activation of TLR-2.

A 2005 study conducted by Jugeau et al built on the study of Kim et al and further demonstrated the role that TLRs play in response to P. acnes.¹² The investigators found that the in vivo expression of TLR-2 and TLR-4 is increased in the acne lesions. In vitro tests also demonstrated that an increase in TLR-2 and TLR-4 expression occurred in human keratinocytes during the first hours of incubation with P. acnes. Additionally, Jugeau et al found that keratinocytes had an increased in vitro expression and secretion of metalloproteinase-9 (MMP-9) when incubated with P. acnes.

A 1992 study found that high levels of the pro-inflammatory cytokine IL-1α were expressed in acne lesions, and those findings were corroborated by Selway et al in 2013 and framed within the paradigm of TLRs playing a role in the inflammatory process that engenders AV.¹³ Selway et al found TLR-2 to be expressed in basal and infundibular keratinocytes, and its activation elicited the release of IL-1α from primary human keratinocytes in vitro.¹⁴ The in vitro exposure of micro-dissected human sebaceous glands to pathogen associated molecular patterns specific for TLR-2 also resulted in the increased expression of IL-1α.

In addition to activating TLRs, P. acnes has been shown to activate nucleotide-binding oligomerization domain-like receptors, or NLRs, which are an important class of inflammasome genes that trigger inflammation and anti-microbial responses. Qin et al stimulated human monocytes with P. acnes, and found that P. acnes-induced NLRP3 activation that resulted in enhanced IL-1β secretion.¹⁵ The investigators also determined that monocytes stimulated with P. acnes upregulated caspase-1 expression that resulted in further IL-1β secretion.

Additionally, the investigators noted a higher cellular expression of NLRP-3 and active caspase-1 in the dermis surrounding the pilosebaceous follicles in acne lesions compared with normal skin controls, and also a higher prevalence of CD68+ monocytes/macrophages in acne lesions compared with normal skin controls. Qin et al determined that P. acnes triggers a key inflammatory mediator, IL-1β, via NLRP-3 and caspase-1 activation, indicating a role for inflammasome-mediated inflammation in acne pathogenesis. A second study, conducted by Kistowska et al, has also demonstrated that NLRP-3 and IL-1β are integral to the inflammatory process induced by P. acnes.¹⁶

P. acnes has been shown to produce exogenous proteases, and Lee et al investigated the function of these proteases in the induction of inflammatory cascades. The Lee et al study found that P. acnes protease and proteinase-activated receptor-2 (PAR-2) activity were increased on keratinocytes in AV.¹⁷ Furthermore, keratinocytes that had increased PAR-2 activity stimulated the mRNA expression of IL-1α, IL-8, tumor necrosis factor- α (TNF-α), human beta defensin-2, LL-37, MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13. The results of this study indicate that PAR-2 plays an important role in the pathogenesis of AV by inducing inflammatory mediators in response to P. acnes proteases. The study also indicates that some of the inflammatory mediators that are augmented by PAR-2 activity are integral to AV prior to the presence of P. acnes, so P. acnes is merely enhancing their response.

An article by Kim et al, published in Dermatology, was referenced earlier regarding P. acnes inducing NF-κB activation via TLR-2. A subsequent study by Kang et al also demonstrated that NF-κB and activator protein-1 are activated in acne lesions.¹⁸ Kang et al found that TNF-α and IL-1β secretion, which are the resultant effect of NF-κB activation, will further amplify the NF-κB signaling pathways that originally led to their production and stimulate nearby cells for additional pro-inflammatory responses.