Trends in Cell Biology
Update
Research FocusSunburned skin activates inflammasomes
Research Focus
Introduction
Most Caucasians have a love–hate relationship with the sun. We aspire to acquire lovely tanned skin but often suffer the consequences of sunburn – not to mention the increased risk of skin cancers. In this context, ultraviolet (UV)-irradiation is both friend and foe, stimulating melanocytes to produce melanin (the pigment that imparts brown color), although also damaging DNA and other macromolecules, leading to tissue injury. A recent report by Feldmeyer, Beer and colleagues implicates interleukin (IL)-1β that is secreted from UV-irradiated keratinocytes in sunburn-associated inflammation and demonstrates a prominent role for caspase-1-activating NOD-like receptor (NLR)-family proteins in sunburn-associated inflammation [1]. Hence, NLRs are emerging as crucial links between cell injury and inflammation, in addition to their roles in sensing microbial products in the context of innate immunity.
Section snippets
Inflammasomes and caspase-1 activation
Caspase-1 is an intracellular protease that cleaves the precursors of IL-1β, IL-18 and IL-33 to yield active proinflammatory cytokines [2]. Caspase-1 makes important contributions to host defense [3], however, it also has a causative role in several acute and chronic inflammatory diseases 4, 5, as demonstrated by experiments using caspase-1-deficient mice. These mice have a normal phenotype but they are resistant to endotoxic shock and some types of additional insults. Caspase-1 is synthesized
UVB exposure triggers NLR-dependent IL-1β secretion from human keratinocytes
Keratinocytes are the first cells to encounter many pathogens, so it is logical that they should be armed with molecules involved in innate immunity. Recent reports show that all of the essential inflammasome components are expressed in cultured human primary keratinocytes, including the NLR-family member NALP1 (NLRP1), the adaptor protein apoptosis-associated speck-like protein (ASC), pro-caspase-1 and pro-IL-1β [13]. However, although NALP1 is expressed constitutively in these epithelial
Danger signals, microbial products and ion homeostasis
It makes sense that tissue injury, such as sunburn, should trigger an inflammatory response, involving cytokines, such as IL-1β; however, why, of the 22 human NLRs, are NALP1 and NALP3 involved in the keratinocyte response to UV-irradiation? Earlier studies suggested that NALP1 and NALP3 can be activated by muramyl-dipeptide (MDP), a component of bacterial peptidoglycan, in a LRR domain-dependent manner 10, 15, which fits with the notion that NLR-family proteins represent a first-line of
Keratinocytes spit out inflammasomes
When we eat something harmful, our body tends to expel it. Feldmeyer, Beer and colleagues show that UV-irradiated keratinocytes release inflammasome components, including NALP1, ASC and caspase-1, thus extending earlier studies with macrophages that showed secretion of ASC and caspase-1 [19] to now include NLR-family proteins. The release of NALP1 and other inflammasome components into the extracellular medium does not appear to involve cell death, as demonstrated by measurements of culture
Of mice and men
Biologists studying inflammation rely heavily on Mus musculus, the laboratory mouse, for gaining insights into the complex workings of the immune system. However, when it comes to NLR-family proteins, the analogies between mice and humans quickly breakdown. For starters, the human genome contains 22 NLR-encoding genes, whereas mice have 34 genes and their encoded proteins are often considerably divergent compared with their human counterparts – so much so that many NLRs in mice are best
Conclusions
Although studied extensively in macrophages, many NLRs are also expressed in epithelial tissues, in which they presumably represent a first line of defense against the threats of the outside world. The recent report of NLR involvement in inflammatory cytokine elaboration in the context of UV-irradiation provides another illustration of diverse roles of these proteins in marshalling inflammatory responses, beyond microbial surveillance. Understanding how NLRs become activated by cell injury is
Acknowledgements
We thank the NIH (AI-056324, CA-69381) for their generous support and the Crohn's and Colitis Foundation of America.
References (27)
The inflammasome mediates UVB-induced activation and secretion of interleukin-1β by keratinocytes
Curr. Biol.
(2007)Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock
Cell
(1995)- et al.
NLRs join TLRs as innate sensors of pathogens
Trends Immunol.
(2005) Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation
Mol. Cell
(2007)Activation of the IL-1β-processing inflammasome is involved in contact hypersensitivity
J. Invest. Dermatol.
(2007)Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome
Curr. Biol.
(2004)Altered cytokine production in mice lacking P2X(7) receptors
J. Biol. Chem.
(2001)Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase-1
Immunity
(2006)Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1
Cell
(2007)Caspases: opening the boxes and interpreting the arrows
Cell Death Differ.
(2002)
Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis
J. Exp. Med.
IL-1β-converting enzyme (caspase-1) in intestinal inflammation
Proc. Natl. Acad. Sci. U. S. A.
CATERPILLERs, pyrin and hereditary immunological disorders
Nat. Rev. Immunol.
Cited by (79)
Alternative autophagy dampens UVB-induced NLRP3 inflammasome activation in human keratinocytes
2024, Journal of Biological ChemistryTRPV4 Activation Increases the Expression of CD207 (Langerin) of Monocyte-Derived Langerhans Cells without Affecting their Maturation
2023, Journal of Investigative DermatologyThe CARD8 inflammasome in HIV infection
2023, Advances in ImmunologyNLRP1 Inflammasome Activation in Keratinocytes: Increasing Evidence of Important Roles in Inflammatory Skin Diseases and Immunity
2022, Journal of Investigative DermatologyCitation Excerpt :Indeed, already in 2007, it was shown that human primary KCs (HPKs) express inflammasome proteins and high levels of pro‒IL-1β (Feldmeyer et al., 2007). Irradiation of HPKs with a physiologic dose of UVB causes caspase-1 and pro‒IL-1β activation and release of the mature cytokine (Feldmeyer et al., 2007), suggesting that activation of the inflammasome pathway in KCs underlies the induction of sunburn (Faustin and Reed, 2008). Interestingly, HPKs isolated from patients with MSPC/FKLC undergo NLRP1 activation and IL-1β secretion spontaneously (Zhong et al., 2016).
Epithelial Pyroptosis in Host Defense
2022, Journal of Molecular Biology