ABSTRACT
Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1DR) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1DR to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.
Subject(s)
Inflammasomes , MAP Kinase Kinase Kinases , NLR Proteins , Pyroptosis , Ribosomes , Stress, Physiological , Anisomycin/toxicity , CARD Signaling Adaptor Proteins/metabolism , Humans , Inflammasomes/drug effects , Inflammasomes/metabolism , Inflammasomes/radiation effects , Keratinocytes/drug effects , Keratinocytes/metabolism , Keratinocytes/radiation effects , MAP Kinase Kinase Kinases/metabolism , Mutation , NLR Proteins/genetics , NLR Proteins/metabolism , Neoplasm Proteins/metabolism , Phosphorylation/drug effects , Phosphorylation/radiation effects , Pyroptosis/drug effects , Pyroptosis/radiation effects , Ribosomes/drug effects , Ribosomes/radiation effects , Ultraviolet RaysABSTRACT
INTRODUCTION: Urban air quality in South-East Asia is influenced by local and transboundary sources of air pollutants. Research studies have well characterized the short-term effects of air pollution on cardiovascular and respiratory health but less so on ocular health. We investigated the relationship between air pollution and acute conjunctivitis in Singapore, a tropical city-state located in South-East Asia. METHODS: Assuming a negative-binomial distribution, we examined the short-term associations between all-cause acute conjunctivitis reports from 2009 to 2018 and contemporaneous ambient air pollutant concentrations using a time-series analysis. In separate pollutant models for PM2.5 and PM10, we fitted fractional polynomials to investigate the linearity between air pollutant exposures and conjunctivitis, adjusting for long-term trend, seasonality, climate variability, public holidays, immediate and lagged exposure effects, and autocorrelation. RESULTS: There were 261,959 acute conjunctivitis reports over the study period. Every 10 µg/m3 increase in PM2.5 was associated with a 3.8% (Incidence Rate Ratio (IRR): 1.038, 95% Confidence Interval (CI): 1.029-1.046, p < 0.001) cumulative increase in risk of conjunctivitis over the present and subsequent week. Every 10 µg/m3 increase in PM10 was associated with a 2.9% (Incidence Rate Ratio (IRR): 1.029, 95% Confidence Interval (CI): 1.022-1.036, p < 0.001) cumulative increase in risk of conjunctivitis over the present and subsequent week. Acute conjunctivitis reports exhibited an inverse dependence on ambient air temperature and relative humidity variability. Approximately 3% of all acute conjunctivitis reports were attributable to PM2.5. Particulate matter attributed acute conjunctivitis was disproportionately higher during transboundary haze episodes. CONCLUSION: Our study strengthens the evidence linking particulate matter exposure to an increased risk of conjunctival disease, with a disproportionately higher disease burden during South-East Asia transboundary haze episodes. Our findings underscore the importance of reducing the health impact of indigenous and transboundary sources of ambient particulate matter pollution.
