Inflammasomes: key to the engine of skin inflammaging

 The term “inflammaging” has been coined to describe the process of ageing that is driven through inflammatory pathways. While numerous aspects of skin inflammation have been explored, it is curious that, to date, little has been described about one of the most fundamental pathways of skin inflammation signalling and response; Inflammasomes. This paper will describe recent studies we have undertaken looking at how Nod-Like Receptor Protein (NLRP) Inflammasome Complexes form as a result of exogenous contact with various DangerAssociated Molecular Patterns (DAMPs) and Pathogen-Associated Molecular Patterns (PAMPs) and how, after forming, these critical inflammation sentinels release Caspase-1 which commences a powerful pattern of downstream inflammation responses that leads to healing and, in some cases, over-healing. The link between the formation of NLRP Inflammasomes and such critical skin health responses will be explored as will the link between formation of Inflammasome expressed Caspase-1 and such important skin maladies as acne, rosacea, dandruff, atopic dermatitis, psoriasis, and skin inflammaging will be discussed.

In 2002, Martinon et al., described the discovery of the Nod-Like Receptor Protein (NLRP) Inflammasome Complexes and in 2009 the same group recognised more fully the importance of these critical sentinel complexes in the body’s inflammatory response that they labelled them: “the guardians of the body”.1,2 In 2008, Faustin et al., recognised that skin cells, like keratinocytes and fibroblasts, responded to UV energy by activating the NLRP Inflammasome Complex.3 This directly linked the activity of the skin’s two primary cell types to a direct response, outside of the normal dendritic cellular response, to the threat of UV energy. More recently, Li et al., reported that NLRP inflammasomes are activated in human sebocytes directly by exposure to Propionibacterium acnes.4 This study directly links the impact of the skin’s microbiome to a microorganism that can become pathogenic. In 2011, Dayan and Wertz published the book Innate Immune System of Skin and Oral Mucosa. Nowhere within the chapters of this book was there mentioned the critical element of the skin’s innate immune response through the NLRP Inflammasome pathways.5 This reflects the fact that the link between skin health and the NLRP Inflammasomes was not apparent even though it had been discovered in 2008 that both keratinocytes and fibroblasts expressed these unique inflammatory complexes. 

To date, studies have looked at the role of the NLRP Inflammasomes in skin health through their action in keratinocytes.6,7 These recent discussions are focused on determining if it is the NLRP1 or NLRP3 inflammasomes that are most responsible for skin health. This paper will discuss our recent work with a new, rapid bioluminescent assay that allows for examination of the release of active Caspase-1 from NLRP-inflammasome activated Normal Human Epidermal Keratinocytes (NHEK). Early discussion of this work has appeared previously.8-10 This paper will help to bring these earlier discussions into a more practical and pragmatic discussion on the role of inflammation in skin ageing and health.