Porphyrins produced by acneic Cutibacterium acnes strains activate the inflammasome by inducing K+ leakage

Abstract

Summary Some Cutibacterium acnes subgroups dominate on healthy skin, whereas others are frequently acne associated. Here we provide mechanistic insights into this difference, using an anaerobic keratinocyte-sebocyte- C. acnes co-culture model. An acneic C. acnes strain as well as its porphyrins activates NRLP3 inflammasome assembly, whereas this was not observed with a non-acneic strain. Low levels of intracellular K + in keratinocytes stimulated with extracted porphyrins or infected with the acneic strain were observed, identifying porphyrin-induced K + leakage as trigger for inflammasome activation. Using a panel of C. acnes strains, we found that porphyrin production and IL-1β release are correlated and are higher in acneic strains. This demonstrates that the latter produce more porphyrins, which interact with the keratinocyte cell membrane, leading to K + leakage, NLRP3 inflammasome activation, and IL-1β release and provides an explanation for the observation that some C. acnes strains are associated with healthy skin, whereas others dominate in acneic skin.

Antibacterial Activity of the Essential Oil From Litsea cubeba Against Cutibacterium acnes and the Investigations of Its Potential Mechanism by Gas Chromatography-Mass Spectrometry Metabolomics

“…Apart from the above, amino acid metabolism also involves the synthesis of virulence factors in bacteria. C. acnes can secrete porphyrin, hyaluronidase, lipase, and others to cause cell inflammation, which is closely related to the pathogenesis of acne ( De Canha et al, 2019 ; Spittaels et al, 2021 ). The disorder of amino acid metabolism may inhibit the ability of bacteria to secrete virulence factors and reduce their pathogenicity.…”

Expert Recommendations on the Evaluation of Sunscreen Efficacy and the Beneficial Role of Non-filtering Ingredients

“…Such an imbalance may also accelerate photocarcinogenesis ( 91 ). For example, Cutibacterium acnes produce less porphyrins when irradiated with UVB photons ( 92 ), which may lead to decreased inflammatory responses ( 93 ). Other symbiotic yeast and bacteria are also affected by UV radiation, unbalancing the skin microbiome and favoring the onset of skin cancer, particularly those related to virus, e.g., HPV and Merkel cell polyomavirus ( 94 ).…”

The immunomodulatory potential of phage therapy to treat acne: a review on bacterial lysis and immunomodulation

“…Inflammation is induced by secretion of the virulence factors, and skin and immune cells’ recognition of bacterial PAMPs, triggering the activation of innate immune cells. Porphyrins produced by isolates belonging to the IA 1 phylotype induces perturbations on keratinocyte membrane integrity, resulting in IL-1β production ( Spittaels et al, 2021 ). Other virulence factors may play relevant roles in acne pathogenesis, although their exact role is not fully understood.…”

“…This would represent a change in the classic viewpoint of selecting phages for phage therapy with a broad host range ( Fernández et al, 2019 ), since healthy skin is characterized by a high diversity of phylotypes, in particular abundance of II and III phylotypes ( Barnard et al, 2016 ). Therefore, selection of C. acnes phages should focus on those specific for strains belonging to phylotype I, aiming to restore skin microbial homeostasis and diminish exposure to virulence-bearing isolates that promote inflammation ( Spittaels et al, 2021 ). Nonetheless, this approach must be further explored due to the limited genetic diversity of C. acnes phages.…”