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  • Title: Cigarette smoke-induced inflammation: NLRP10-mediated mechanisms.
    Author: Kaur G, Bagam P, Pinkston R, Singh DP, Batra S.
    Journal: Toxicology; 2018 Apr 01; 398-399():52-67. PubMed ID: 29501574.
    Abstract:
    Chronic obstructive pulmonary disease (COPD) is a progressive, life-threatening disease that causes irreversible lung damage. Cigarette smoking is the chief etiologic factor for the commencement of this condition. Despite constant efforts to develop therapeutic interventions and to ascertain the molecular mechanism leading to the pathophysiology of this disease, much remains unknown. However, pattern recognition receptors (PRRs), i.e., Toll-like-receptors (TLRs) and NOD-like receptors (NLRs) are believed to play important roles in COPD and could serve as effective therapeutic targets. Although the role of TLRs in COPD has been well studied, the importance of NLRs has not yet been explored in detail. The NLR family member NLRP10 (aka NOD8, PAN5, PYNOD) is the only member of this family of proteins that lacks the leucine rich repeat (LRR) domain responsible for detection of pathogen and danger-associated molecular patterns (PAMPs/DAMPs). Therefore, instead of functioning as a PRR, NLRP10 may have a broader regulatory role. To elucidate the role of NLRP10 in secondhand smoke (SHS)-induced inflammation, we exposed C57Bl/6 (WT) and Nlrp10-deficient mice (Nlrp10-/-) on the C57Bl/6 background to filtered air- or SHS- for 6 weeks (acute exposure) and assessed the resulting molecular events. Leukocyte recruitment in SHS-exposed Nlrp10-/- mice was found to be significantly lower compared to SHS-exposed WT mice. In addition, we observed an important role for NLRP10 in SHS-mediated caspase-1 activation, cytokine/chemokine production (IL-1β, IL-18, MCP-1 and IL-17A), and induction of NF-κB and MAPKs in the lungs of C57Bl/6 mice. The reduced influx of CD4+IL-17A+ and CD8+IL-17A+ cells into the lungs of SHS-exposed Nlrp10-/- mice and impaired differentiation of Nlrp10-/- Th0 cells into Th17 cells (ex vivo) provide insight into the mechanistic details underlying NLRP10-dependent IL-17 production. We further substantiated our in vivo findings by challenging human alveolar type II epithelial cells (A549) transfected with scrambled- or Nlrp10-siRNA with cigarette smoke extract (CSE). We observed an important role of NLRP10 in cytokine and chemokine production as well as expression of NF-κB and MAPKs in CSE-exposed A549 cells. Furthermore, replenishment of A549 cell culture with recombinant IL-17A (rIL-17A) during NLRP10 knockdown rescued CSE-induced inflammatory responses. To identify upstream mediators of NLRP10 regulation we investigated epigenetic markers within the Nlrp10 promoter following cigarette smoke exposure and observed significant changes in active as well as repressive gene markers on histone 3 and histone 4 using both in vivo and in vitro study models. Further, alterations in the respective histone acetyl- and methyltransferases (PCAF, SET1, ESET, SUV20H1) correlated well with the observed histone modifications. Overall, our findings suggest a novel role of epigenetically regulated NLRP10 in Th17/IL-17 signaling during CS exposure.
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