NLRP1 and NLRP3 inflammasomes as a new approach to skin carcinogenesis

Abstract

Inflammasomes are key innate immune system receptors that detect pathogenic endo- and exogenous stressors like microorganisms or ultraviolet radiation (UVR) which activate the highly proinflammatory cytokines interleukin-1β and interleukin-18. Inflammasomes are not only involved in inflammation, but also in carcinogenesis and tumor progression. Due to the dynamic increase in non-melanoma skin cancers (NMSC), it has become necessary to determine how UVR, which plays a key role in NMSC development, can regulate the structure and function of inflammasomes. In the present study, the regulatory mechanisms of NOD-Like Receptor Family Pyrin Domain Containing 1 and 3 inflammasome activation as well as an effective inflammasome-mediated immune response after UVR exposition are discussed. The differences and similarities between these molecular complexes that monitor cellular health, inflammation, and skin carcinogenesis are also highlighted. Despite numerous scientific data, more studies are still required to better understand the biology of inflammasomes in skin cancer development and to explore their therapeutic potential.

Keywords: NLRP1; NLRP3; UVR; inflammasome; skin carcinogenesis.

Figure 1.

Schematic representation of NLRP1 and NLRP3 inflammasomes. All NLRP1 inflammasomes are composed of NACHT, LRR, FIIND and CARD domains. Domain positions are indicated to scale. The presence of FIIND and CARD domains at the C-terminus makes NLRP1 stand out from all other members of the NLR family. However, the NLRP1 inflammasome is quite different in murine and human models. (A-a) Mouse NLRP1 inflammasome: In mice, there are three paralogs of NLRP1 (Nlrp1a, -b, and -c) which contain an NR100 domain instead of the PYD found in humans. Mouse NLRP1 can activate caspase-1 directly and ASC (apoptosis associated with Speck-like protein) is not required. (A-b) Human NLRP1 inflammasome: Human NLRP1 contains the N-terminal PYD. Its activity is dependent upon ASC, which is associated with the C-terminal CARD domain. (B) NLRP3 inflammasome: The NLRP3 inflammasome consists of an NLRP3 protein, an ASC adaptor, and procaspase-1. Upon stimulation, NLRP3 and ASC adhere via their PYD domains, whereas ASC and caspase-1 adhere via their CARD domains. Therefore, NLRP3 forms an ASC-dependent inflammasome. NLRP1, NOD-like receptor family pyrin domain containing 1; NLRP3, NOD-like receptor family pyrin domain containing 3; NACHT, nucleotide-binding and oligomerization domain; LRR, leucine rich repeat; FIIND, function to find domain; PYD, pyrin domain; ASC, apoptosis associated with Speck-like protein.

Figure 2.

Activation of NLRP1 and NLRP3 inflammasomes. UVR irradiation of human keratinocytes may trigger the assembly of NLRP1 and NLRP3 inflammasomes. The NLRP1 inflammasome complex consists of caspase-1, ASC (which is not required to form complexes in murine) and NLRP1. The exact role of caspase-5 in NLRP1 inflammasome activation is unclear. The NLRP3 inflammasome is well characterized among the inflammasome complexes and consists of NLRP3, ASC and caspase-1. An active caspase-1 form is required to process pro-IL-1β and pro-IL-18 into mature forms and to secrete them into the extracellular space. Furthermore, inflammasome is associated with the unconventional secretion of HMGB-1. Active caspase-1 can lead to cell pyroptosis with membrane rupture and the release of alarmins, such as HMGB1. NLRP1, NOD-like receptor family pyrin domain containing 1; NLRP3, NOD-like receptor family pyrin domain containing 3; UVR, ultraviolet radiation; ASC, apoptosis associated with Speck-like protein; HMGB-1, high mobility group box protein 1; IL, interleukin.