Resistance to Prostaglandin E2 Promotes Monocyte Activation During Chronic HIV Infection

DI DIEGO GARCIA, FACUNDO; CABRERIZO, GONZALO; PALETTA, ANA; PÉREZ, PAULA S; VARESE, AUGUSTO; GEFFNER, JORGE; BELLO, NATALIA; FRIDMAN, VANESA; STECHER, DANIEL; CEBALLOS, ANA; REMES LENICOV, FEDERICO

JOURNAL OF INFECTIOUS DISEASES

UNIV CHICAGO PRESS

Año: 2023 vol. 227 p. 423 - 433

0022-1899

AbstractBackground: Monocyte activation is a driver of inflammation in the course of chronic HIV infection. Prostaglandin E2 (PGE2) is known to mediate anti-inflammatory effects, notably the inhibition of tumor necrosis factor- (TNF-) production by monocytes. We aim to investigate the effects of PGE2 on activation of monocytes in chronic HIV infection and the mechanisms through which PGE2 modulates their inflammatory signature.Methods: We recruited a group of people with HIV (PWH) and matched healthy uninfected persons. We compared plasma levels of PGE2, monocyte activation, and sensitivity of monocytes to the inhibitory actions mediated by PGE2.Results: We found increased plasma levels of PGE2 in PWH, and an activated phenotype in circulating monocytes, compared with uninfected individuals. Monocytes from PWH showed a significant resistance to the inhibitory actions mediated by PGE2; the concentration of PGE2 able to inhibit 50 of the production of TNF- by lipopolysaccharide-stimulated monocytes was 10 times higher in PWH compared with uninfected controls. Furthermore, the expression of phosphodiesterase 4B, a negative regulator of PGE2 activity, was significantly increased in monocytes from PWH.Conclusions: Resistance to the inhibitory actions mediated by PGE2 could account, at least in part, for the inflammatory profile of circulating monocytes in PWH.Keywords: PDE4; TNF-α; chronic HIV infection; desensitization; inflammation; monocytes; phosphodiesterases; prostaglandin e2.