Full Papers
Soluble TREM-1 ameliorates gouty arthritis by selective inhibition of proinflammatory cytokines and chemokines without affecting TGFβ production.
Y. Molad1, I. Lagovsky2
- Laboratory for Research of Inflammation, Felsenstein Medical Research Center, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv; and Institute of Rheumatology, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel. ymolad@tauex.tau.ac.il
- Laboratory for Research of Inflammation, Felsenstein Medical Research Center, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
CER18221
Full Papers
Received: 09/10/2024
Accepted : 21/02/2025
In Press: 23/04/2025
Abstract
OBJECTIVES:
TREM-1 is upregulated in MSU crystal-induced activation of myeloid cells in gouty arthritis. The aim of the study was to determine the effect of TREM-1 blockade on proinflammatory cytokines and chemokines production as well as anti-inflammatory TGFβ in gout.
METHODS:
Undifferentiated monocyte THP-1 cells were incubated with an agonist anti-TREM-1 antibody, synthetic peptide LP17 (TREM-1 inhibitor), or isotype-matched control followed by stimulation with MSU crystals, and changes in mRNA levels and protein expression of the relevant cytokines and chemokines were evaluated by RT-PCR and ELISA, respectively. A murine air-pouch model of MSU crystal-induced inflammation with LP17-mediated inhibition of TREM1 was analysed for cytokine level (ELISA) and TREM-1 expression (FACS).
RESULTS:
MSU crystal-induced THP-1 monocyte activation upregulated mRNA and protein levels of TREM-1, IL-1β, TNFα, IL-8, and CCL3, as well as TGFβ. Co-stimulation with an agonist anti-TREM-1 antibody amplified the effect of MSU crystals on IL-1β, TNFα, IL-8, and CCL3 expression, with no significant effect on TGFβ expression. Blockade of monocyte TREM-1 using LP17 had a significant suppressive effect on the expression of IL-1β, TNFα, IL-8, and CCL3, but not TGFβ. In the in vivo air-pouch murine model, LP17 ameliorated MSU crystal-induced inflammation by diminishing the recruitment of leucocytes and significant reduction of proinflammatory cytokine and chemokine level, with no inhibitory effect on TGFβ level.
CONCLUSIONS:
TREM-1 blockade (LP17) in gouty arthritis selectively inhibits proinflammatory cytokines and chemokines, whereas the level of TGF β remains unaffected. Thus, LP17 induces a shift towards anti-inflammatory cytokine TGFβ that results in spontaneous resolution of the gout attack.
