stimulate pro-inflammatory cytokine release.79,80 They also bind to the peroxisome proliferator activated receptor-gamma (PPAR-gamma), triggering the production of lipids from sebocytes.84 Activation of PPAR-gamma has also been shown to be involved in androgen-mediated signaling and regulation of glucose and lipid metabolism, once again suggesting cross-talk between many potential pathophysiologic cascades in the development of AV.74 Interestingly, these links on cursory review appear to be unrelated and involve distinctly different body systems and functions, however, cross-talk that can affect pathophysiology has been identified.
Immune Function
Immunologic responses, both local and systemic, have become progressively recognized as important in AV pathophysiology. Studies suggest that C. acnes can trigger immune responses in AV through multiple, direct pathways.12,60 A primary immune response occurs through interaction with specific TLRs, which are innate pattern recognition receptors, expressed on numerous cell types present within the skin, such as keratinocytes, sebocytes, dendritic cells, lymphocytes, mast cells, and resident macrophages.60 The innate immune system also responds to C. acnes proliferation and cellular interactions through inflammasomes -- receptors that induce inflammation in response to microbes, and by stimulating antimicrobial peptide (AMP) activity, small molecules that have a wide range of inhibitor effects against bacteria, fungi, parasites, and viruses, but can respond in disease states such as AV that involve a pathogenic commensal organism.60 Finally, C. acnes induces the production of MMPs, which are zinc-dependent protease enzymes that can degrade many structural components of the extracellular skin matrix, with involvement in modulation of AV-affected skin including potential scarring.60,85
Subclinical inflammation of the skin begins early in the development of AV.12,74 Based on data evaluating the sequence of AV lesion formation, perilesional lymphocyte accumulation with the recruitment of inflammatory mediators is thought to precede or occur simultaneously with follicular hyperkeratinization (microcomedone formation) in the PSU. In vitro studies show that the application of pro-inflammatory cytokines such as IL-1 on PSU induces hyperkeratinization.85 In addition, other pro-inflammatory cytokines such as TNF-alpha and interleukins such as IL-8 have been shown to be higher in AV lesions compared to uninvolved skin, suggesting that many cytokines and other mediators contribute collectively to the development of AV lesions.86
Beyond the direct involvement of the immune-inflammatory response at the PSU, other noxious stimuli indirectly trigger heightened immune responses. Oxidative stress causes direct and immunologic cellular damage.77 Microbiome dysbiosis can activate the innate immune system to defend from proliferation of pathogenic microbial organisms.65 High glycemic index diets and insulin fluctuations can induce a generalized inflammatory response, and stress can promote a heightened immune response on both local and systemic levels.36,42 DHT upregulates sebaceous lipid formation and pro-inflammatory cytokine production (ie, TNF-alpha, IL-6) by sebocytes on the PSU, supporting a link between hormonal interactions and an immune-inflammatory response.71 Once activated, many inflammatory mediators such as TNF-alpha, IL-6, SP, and TGF-beta, are expressed, generating "a pro-inflammatory soup" at the PSU.27 With this, neutrophils are recruited to the site of inflammation, further damaging the sebaceous gland and follicular epithelium.27 This follicular wall damage causes porosity within the wall structure, resulting in leakage of follicular contents into the surrounding dermis which induces both direct and indirect inflammation, even in the absence of obvious follicular wall rupture.12
CONCLUSION
The underlying causes of AV have conventionally focused on the major individual pillars of pathophysiology and how individual medications can mitigate these pathways to improve AV. In this article, this prior approach is not discarded. Rather, there is a strong suggestion, with good underlying support, to integrate a more comprehensive management approach to include other underlying systemic factors, many of which are likely to relate directly to AV. In this review, we have identified the 6 major underlying patient-centric factors: psycho-emotional stress, diet and metabolism, hormonal fluctuations, microbiome dysbiosis of the skin and gut, oxidative stress, and immunologic responses. Each of these contributes to an overall generalized dysregulation that includes a variety of immunologic and inflammatory responses, with many believed to contribute to the development and/or exacerbation of AV. This broadened perspective on AV management allows for a more expanded therapeutic approach, beyond only the long-standing conventional method of matching medications with what visible AV lesions are present, coupled with good general skin care.
As a second part of this review, Burgess et al87 will present supporting clinical evidence for various ingredients to address these 6 underlying patient-centric factors.
As a second part of this review, Burgess et al87 will present supporting clinical evidence for various ingredients to address these 6 underlying patient-centric factors.
DISCLOSURES
Dr Del Rosso and Dr Harper are clinical investigators for Nutraceutical Wellness LLC but have not received compensation or services for any aspect of the submitted work. Dr Farris is a paid advisor for Nutrafol and Nutraceutical Wellness LLC. Dr Baldwin declares no conflict of interest. Dr Hazan and Dr Raymond are employees of Nutraceutical Wellness LLC.
ACKNOWLEDGMENT
The authors acknowledge the support of Nicole Townsend and Ryan McLendon for their research assistance.
