Evidence in Favor of an Alternative Glucocorticoid Synthesis Pathway During Acute Experimental Chagas Disease

DA SILVA OLIVEIRA BARBOSA, ESDRAS; ROGGERO, EDUARDO A.; GONZÁLEZ, FLORENCIA B.; FERNÁNDEZ, ROCÍO DEL VALLE; CARVALHO, VINICIUS FRIAS; BOTTASSO, OSCAR A.; PÉREZ, ANA R.; VILLAR, SILVINA R.; COLABORACIÓN TÉCNICA: MARISA E. DERIO

FRONTIERS IN NEUROENDOCRINOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2020 vol. 10

0091-3022

It is well-established that infectious stress activates the hypothalamus?pituitary?adrenalaxis leading to the production of pituitary adrenocorticotropin (ACTH) and adrenalglucocorticoids (GCs). Usually, GC synthesis is mediated by protein kinase A (PKA)signaling pathway triggered by ACTH. We previously demonstrated that acute murineChagas disease courses with a marked increase of GC, with some data suggestingthat GC synthesis may be ACTH-dissociated in the late phase of this parasitic infection.Alternative pathways of GC synthesis have been reported in sepsis or mental diseases,in which interleukin (IL)-1β, prostaglandin E2 (PGE2), and/or cAMP-activated guaninenucleotide exchange factor 2 (EPAC2) are likely to play a role in this regard. Accordingly,we have searched for the existence of an ACTH-independent pathway in an experimentalmodel of a major parasitic disease like Chagas disease, in addition to characterizingpotential alternative pathways of GC synthesis. To this end, C57BL/6 male mice wereinfected with T. cruzi (Tc), and evaluated throughout the acute phase for severalparameters, including the kinetic of GC and ACTH release, the adrenal level of MC2R(ACTH receptor) expression, the p-PKA/PKA ratio as ACTH-dependent mechanism ofsignal transduction, as well as adrenal expression of IL-1β and its receptor, EPAC2 andPGE2 synthase. Our results reveal the existence of two phases involved in GC synthesisduring Tc infection in mice, an initial one dealing with the well-known ACTH-dependentpathway, followed by a further ACTH-hyporesponsive phase. Furthermore, inflamedadrenal microenvironment may tune the production of intracellular mediators that alsooperate upon GC synthesis, like PGE2 synthase and EPAC2, as emerging driving forcesfor GC production in the advanced course of Tc infection. In essence, GC productionseems to be associated with a biphasic action of PGE2, suggesting that the effect ofPGE2/cAMP in the ACTH-independent second phase may be mediated by EPAC2