Epidermal keratinocytes sense dsRNA via the NLRP3 inflammasome, mediating interleukin (IL)‐1β and IL‐18 release

Abstract

Skin epidermis, in addition to its barrier function, is able to actively sense harmful pathogens using pattern recognition receptors. In immune cells, the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome can mediate innate immunity against viral infection via a mechanism involving viral dsRNA recognition. Epidermal keratinocytes express NLRP3 inflammasome, which can sense contact sensitizers and mite allergens, leading to pro-interleukin (IL)-1β and pro-IL-18 cleavage into their active forms. Skin often faces viral infection. However, it is unknown whether viral dsRNA can be detected by the keratinocyte NLRP3 inflammasome. We transfected polyinosinic:polycytidylic acid (poly I:C), a synthetic viral dsRNA analogue, into cultured primary human keratinocytes at the aid of Lipofectamine 2000, and found that transfected poly I:C activated caspase-1 and induced caspase-1-dependent release of IL-1β and IL-18, which were suppressed on transfection with NLRP3 siRNA. The activation of keratinocyte NLRP3 inflammasome by transfected poly I:C was dependent on dsRNA-induced protein kinase (PKR) activation, and priming with type I interferons upregulated NLRP3 inflammasome activation through promoting PKR activation in poly I:C-transfected keratinocytes. In conclusion, the NLRP3 inflammasome can act as a sensor of dsRNA in epidermal keratinocytes, which may be important in both skin innate immune defense against viral infection and skin inflammation.

The p38 Mitogen-Activated Protein Kinase Critically Regulates Human Keratinocyte Inflammasome Activation

“…Indeed, keratinocytes are immunologically active cells equipped with functional pattern recognition receptors, including the NOD-like receptor (NLR) family that, in their function as essential components of the inflammasome, can sense and respond to various environmental stimuli. These include UVB (290e320 nm) (Feldmeyer et al, 2007), microbes (Reinholz et al, 2013;Soong et al, 2012), bee venom (Dombrowski et al, 2012), viral double-stranded RNA (Dai et al, 2017), irritants such as chromium (Adam et al, 2017), and contact sensitizers (Watanabe et al, 2007), but also to endogenous stimuli such as cytosolic DNA (Dombrowski et al, 2011;Goblos et al, 2016) or serum amyloid A (Yu et al, 2015). In myeloid cells, a broad range of stimuli can trigger inflammasome activation, especially the NLRP3 inflammasome.…”

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

“…There is evidence that GSDMD forms also pores in organelles, leading to the decay of mitochondria and lysosomes prior to the rupture of the plasma membrane . Many components of the pyroptotic molecular machinery are expressed and can be activated in epidermal keratinocytes . A homolog of GSDMD, GSDMA, is expressed specifically in keratinocytes and it will be important to determine whether GSDMA contributes to the subcellular changes during differentiated‐associated cell death of keratinocytes in the epidermis and skin appendages.…”

“…[28] Many components of the pyroptotic molecular machinery are expressed and can be activated in epidermal keratinocytes. [29][30][31][32][33] A homolog ? UCA of GSDMD, GSDMA, is expressed specifically in keratinocytes [33][34][35][36] and it will be important to determine whether GSDMA contributes to the subcellular changes during differentiated-associated cell death of keratinocytes in the epidermis and skin appendages.…”

Lichen planus: altered AIM 2 and NLRP 1 expression in skin lesions and defective activation in peripheral blood mononuclear cells

“…Inflammasome components can sense a broad range of microorganisms and tissue stress via mechanisms such as the recognition of pathogen‐associated molecular patterns (PAMPs) and danger‐associated molecular patterns (DAMPs), respectively. The inflammasome contains nucleotide‐binding domains, leucine‐rich repeat‐containing family members, and pyrin domains that recognize unique bacterial and danger components, and may play important roles in the innate immune defences of skin against bacterial and viral infection as well as in skin inflammation . Inflammasome stimulation results in the activation of pro‐caspase‐1 to form caspase‐1 and the production and secretion of mature interleukin (IL)‐1β and IL‐18.…”

“…The inflammasome contains nucleotide-binding domains, leucine-rich repeat-containing family members, and pyrin domains that recognize unique bacterial and danger components, and may play important roles in the innate immune defences of skin against bacterial and viral infection as well as in skin inflammation. 1 Inflammasome stimulation results in the activation of pro-caspase-1 to form caspase-1 and the production and secretion of mature interleukin (IL)-1b and IL-18. NACHT, LRR and PYD domains-containing protein (NLRP)1, a component of the inflammasome, is thought to be a prominent inflammasome sensor in human skin.…”