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In vitro sepsis up-regulates Nociceptin/Orphanin FQ receptor expression and function on human T- but not B-cells.
- Source :
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British journal of pharmacology [Br J Pharmacol] 2023 Sep; Vol. 180 (17), pp. 2298-2314. Date of Electronic Publication: 2023 May 11. - Publication Year :
- 2023
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Abstract
- Background and Purpose: In animal models of sepsis, increased activation of the Nociceptin/Orphanin FQ (N/OFQ) receptor NOP is associated with mortality and NOP antagonists improved survival. We have explored the role of the N/OFQ-NOP system in freshly isolated volunteer human B- and T-cells incubated with lipopolysaccharide (LPS) and peptidoglycan G (PepG) as a model of in vitro sepsis.<br />Experimental Approach: B- and T-cell NOP expression was measured using the NOP fluorescent probe N/OFQ <subscript>ATTO594</subscript> , N/OFQ content was measured using immunofluorescence, N/OFQ release was tracked using a CHO <subscript>hNOPGαiq5</subscript> biosensor assay and NOP function was measured using transwell migration and cytokine/chemokine release using a 25-plex assay format. Cells were challenged with LPS/PepG.<br />Key Results: CD19-positive B-cells bound N/OFQ <subscript>ATTO594</subscript> ; they also contain N/OFQ. Stimulation with CXCL13/IL-4 increased N/OFQ release. N/OFQ trended to reduced migration to CXCL13/IL-4. Surface NOP expression was unaffected by LPS/PepG, but this treatment increased GM-CSF release in an N/OFQ sensitive manner. CD3-positive T-cells did not bind N/OFQ <subscript>ATTO594</subscript> ; they did contain N/OFQ. Stimulation with CXCL12/IL-6 increased N/OFQ release. When incubated with LPS/PepG, NOP surface expression was induced leading to N/OFQ <subscript>ATTO594</subscript> binding. In LPS/PepG-treated cells, N/OFQ reduced migration to CXCL12/IL-6. LPS/PepG increased GM-CSF release in an N/OFQ sensitive manner.<br />Conclusions and Implications: We suggest both a constitutive and sepsis-inducible N/OFQ-NOP receptor autocrine regulation of B- and T-cell function, respectively. These NOP receptors variably inhibit migration and reduce GM-CSF release. These data provide mechanistic insights to the detrimental role for increased N/OFQ signalling in sepsis and suggest a potential role for NOP antagonists as treatments.<br /> (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 180
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 37021779
- Full Text :
- https://doi.org/10.1111/bph.16088