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NLRC4 Inflammasome-Mediated Regulation of Eosinophilic Functions

  • Ilgin Akkaya (Department of Molecular Biology and Genetics, Istanbul Technical University) ;
  • Ece Oylumlu (Department of Molecular Biology and Genetics, Istanbul Technical University) ;
  • Irem Ozel (Department of Molecular Biology and Genetics, Istanbul Technical University) ;
  • Goksu Uzel (Department of Molecular Biology and Genetics, Istanbul Technical University) ;
  • Lubeyne Durmus (Department of Molecular Biology and Genetics, Istanbul Technical University) ;
  • Ceren Ciraci (Department of Molecular Biology and Genetics, Istanbul Technical University)
  • Received : 2021.08.23
  • Accepted : 2021.10.29
  • Published : 2021.12.31
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Abstract

Eosinophils play critical roles in the maintenance of homeostasis in innate and adaptive immunity. Although primarily known for their roles in parasitic infections and the development of Th2 cell responses, eosinophils also play complex roles in other immune responses ranging from anti-inflammation to defense against viral and bacterial infections. However, the contributions of pattern recognition receptors in general, and NOD-like receptors (NLRs) in particular, to eosinophil involvement in these immune responses remain relatively underappreciated. Our in vivo studies demonstrated that NLRC4 deficient mice had a decreased number of eosinophils and impaired Th2 responses after induction of an allergic airway disease model. Our in vitro data, utilizing human eosinophilic EoL-1 cells, suggested that TLR2 induction markedly induced pro-inflammatory responses and inflammasome forming NLRC4 and NLRP3. Moreover, activation by their specific ligands resulted in caspase-1 cleavage and mature IL-1β secretion. Interestingly, Th2 responses such as secretion of IL-5 and IL-13 decreased after transfection of EoL-1 cells with short interfering RNAs targeting human NLRC4. Specific induction of NLRC4 with PAM3CSK4 and flagellin upregulated the expression of IL-5 receptor and expression of Fc epsilon receptors (FcεR1α, FcεR2). Strikingly, activation of the NLRC4 inflammasome also promoted expression of the costimulatory receptor CD80 as well as expression of immunoregulatory receptors PD-L1 and Siglec-8. Concomitant with NLRC4 upregulation, we found an increase in expression and activation of matrix metalloproteinase (MMP)-9, but not MMP-2. Collectively, our results present new potential roles of NLRC4 in mediating a variety of eosinopilic functions.

Keywords

Acknowledgement

This work was supported by Scientific and Technological Research Council of Turkey (TUBITAK), 3001- Career Development Program Project No: 115Z819; 1001- The Scientific and Technological Research Projects Funding Program Project No: 218S462 and Istanbul Technical University, Scientific Research Projects Department Project No: 42792 to CC. Special Thanks to Dr Deborah J Wessels for language editing and Proffesors Fayyaz S Sutterwala and Suzanne L Cassel for in vivo experiments and scientific discussions.

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