Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-Stimulated NK Cells

ZANETTI, SAMANTA ROMINA; ZIBLAT, ANDREA; TORRES, NICOLÁS IGNACIO; ZWIRNER, NORBERTO WALTER; BOUZAT, CECILIA BEATRIZ

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Rockville, Maryland; Año: 2016

0021-9258

Thehomomeric a7 nicotinic receptor (nAChR) is one of the mostabundant nAChRs in the central nervous system where it contributes tocognition, attention and working memory. α7 nAChR is also present inlymphocytes, dendritic cells (DCs) and macrophages and it is emerging as animportant drug target for intervention in inflammation and sepsis. Naturalkiller (NK) cells display cytotoxic activity against susceptible target cellsand modulate innate and adaptive immune responses through their interactionwith DCs. We here show that human NK cells also express α7 nAChR. α7 nAChR mRNAis detected by RT-PCR and cell surface expression of α7 nAChR is detected byconfocal microscopy and flow cytometry using α-bungarotoxin (α-BTX), a specific antagonist. Both mRNA andprotein levels increase during NK stimulation with cytokines (IL-12, IL-18 andIL-15). Exposure of cytokine-stimulated NK cells to PNU-282987, a specific α7 nAChRagonist, increases intracellular calcium concentration ([Ca2+]i)mainly released fromintracellular stores,indicating that α7 nAChR is functional. Moreover, its activation by PNU-282987plus a specific positive allosteric modulator greatly enhances the Ca2+ responsesin NK cells. Stimulation of NK cells with cytokines and PNU-282987 decreasesNF-kB levels and nuclear mobilization, downregulatesNKG2D receptors, and decreases NKG2D-dependent cell-mediated cytotoxicity and IFN-γproduction. Also, such NK cells are less efficient to trigger DC maturation. Thus,our results demonstrate the anti-inflammatory role of a7nAChR in NK cells and suggest that modulation of its activity in these cellsmay constitute a novel target for regulation of the immune response.