NLRP3 Inflammasome and Allergic Contact Dermatitis: A Connection to Demystify

Abstract

Allergic contact dermatitis is a common occupational disease that manifests as a cell-mediated hypersensitivity reaction following skin exposure to small reactive chemicals termed haptens. Haptens penetrate the stratum corneum and covalently modify proteins in the epidermis, inducing intracellular stress, which further leads to the release of damage-associated molecular patterns (DAMPs), such as uric acid, reactive oxygen species, hyaluronic acid fragments and extracellular adenosine triphosphate (ATP). These DAMPs are recognized by pattern recognition receptors (PRRs) in innate immune cells, namely dendritic cells (DCs), leading to their maturation and migration to the draining lymph nodes where they activate naïve T lymphocytes. Among all PRRs, several studies emphasize the role of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome on the allergic contact dermatitis (ACD) sensitization phase. However, skin allergens—danger signals—NLRP3 inflammasome axis is yet to be completely elucidated. Therefore, in this review, we sought to discuss the molecular mechanisms underlying DAMPs release and NLRP3 inflammasome activation triggered by skin allergens. The elucidation of these key events might help to identify novel therapeutic strategies for ACD, as well as the development of nonanimal alternative methods for the identification and potency categorization of skin sensitizers.

Mast Cells in the Skin: Defenders of Integrity or Offenders in Inflammation?

“…In vitro, the formation and internalization of hapten–protein complexes by human keratinocytes has been shown to result in neoepitope formation [ 276 , 277 , 278 ]. While in vivo, the sequence of events is less understood, epidermal stress responses include inflammasome activation and release of IL-1β and IL-18 [ 279 , 280 ], production of reactive oxygen species (ROS) [ 281 ] and alarmins, e.g., ATP [ 282 , 283 ] and IL-33 [ 284 , 285 , 286 , 287 ]. The subsequent MC activation rapidly elicits skin blood vessel vasodilatation and increased vessel permeability, resulting in biphasic edema formation, peaking on the first 2 h after hapten encounter and followed by a second peak after 24 to 48 h in sensitized mice, that is predominantly driven by histamine effects [ 228 ].…”

The role of interleukin‐1β in the immune response to contact allergens

“…17 During priming, a cell is stimulated through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) by pathogen-associated molecular patterns (PAMPs) and damageassociated molecular patterns (DAMPs). 18,19 Activation of PRRs leads to signaling via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway that upregulates the expression of pro-IL-1β and NOD-like receptor protein 3 (NLRP3). 20 NLRP3 recruits the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD)) that links…”

“…21,22 In the second stages, NLRP3 is activated through different stimuli such as reactive oxygen species (ROS), extracellular ATP, reduced cytosolic potassium levels, sodium urate, and contact allergens. 17,18 Activation of NLRP3 leads to cleavage of pro-caspase-1 to its active form. The active form of caspase-1 then cleaves pro-IL-1β to its active, mature form.…”

Role of nuclear receptor PXR in immune cells and inflammatory diseases

“…Cleaved Gasdermin D is reported to have the ability to punch holes in cell membranes (34,35), which is an underlying prerequisite for pyroptosis (35-37) (Figure 1). Therefore, PXR induced NLRP3 inflammasome activation in activated macrophages might be associated with a large number of inflammatory diseases, such as inflammatory bowel disease (38), atherosclerosis (39), and allergic contact hypersensitivity (40). Moreover, the increased expression of PXR in high-fat diet-treated mice (41), as well as the high levels of NLRP3 inflammasome in macrophages in NAFLD (42), suggested The role of PXR in the regulation of immune cells.…”