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

Summary Some Cutibacterium acnes subgroups dominate on healthy skin while 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 activate NRLP3 inflammasome assembly, while 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, while others dominate in acneic skin.