AUTHOR=Jøntvedt Jørgensen Marthe , Nore Kristin G. , Aass Hans Christian D. , Layre Emilie , Nigou Jérôme , Mortensen Rasmus , Tasken Kjetil , Kvale Dag , Jenum Synne , Tonby Kristian , Dyrhol-Riise Anne Ma TITLE=Plasma LOX-Products and Monocyte Signaling Is Reduced by Adjunctive Cyclooxygenase-2 Inhibitor in a Phase I Clinical Trial of Tuberculosis Patients JOURNAL=Frontiers in Cellular and Infection Microbiology VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.669623 DOI=10.3389/fcimb.2021.669623 ISSN=2235-2988 ABSTRACT=Introduction

Eicosanoids and intracellular signaling pathways are potential targets for host-directed therapy (HDT) in tuberculosis (TB). We have explored the effect of cyclooxygenase 2 inhibitor (COX-2i) treatment on eicosanoid levels and signaling pathways in monocytes.

Methods

Peripheral blood mononuclear cells isolated from TB patients included in a randomized phase I clinical trial of standard TB treatment with (n=21) or without (n=18) adjunctive COX-2i (etoricoxib) were analyzed at baseline, day 14 and day 56. Plasma eicosanoids were analyzed by ELISA and liquid chromatography-mass spectrometry (LC-MS), plasma cytokines by multiplex, and monocyte signaling by phospho-flow with a defined set of phospho-specific antibodies.

Results

Lipoxygenase (LOX)-derived products (LXA4 and 12-HETE) and pro-inflammatory cytokines were associated with TB disease severity and were reduced during TB therapy, possibly accelerated by adjunctive COX-2i. Phosphorylation of p38 MAPK, NFkB, Erk1/2, and Akt in monocytes as well as plasma levels of MIG/CXCL9 and procalcitonin were reduced in the COX-2i group compared to controls.

Conclusion

COX-2i may reduce excess inflammation in TB via the LOX-pathway in addition to modulation of phosphorylation patterns in monocytes. Immunomodulatory effects of adjunctive COX-2i in TB should be further investigated before recommended for use as a HDT strategy.