PARTICIPATION OF NUCLEAR RECEPTORS NR4A IN THE IMMUNE RESPONSE DURING TUBERCULOSIS

FERREIRA, LEMES SIMONE; ARMANDO, MELISA; DERIO, MARISA ; BOTTASSO, OSCAR; PEREZ, ANA ROSA; SANTUCCI, NATALIA

San Luis

Jornada; LXXI Reunión Científica Anual de la Sociedad Argentina de Inmunología SAI; 2023

Universidad Nacional de San Luis-San Luis

Nuclear receptors (NRs) are a superfamily of ligand-dependent transcriptionfactors that bind to numerous kinds of molecules, mostly hydrophobics, and withan important role in the immune endocrine regulation of homeostasis andpathophysiology. Within the NRs, NR4As orphan receptors have emerged asimportant regulators of immune cell polarization in immune response (IR) andinflammation, particularly affecting NF-κB signaling. In macrophages (Mf), NR4Areceptors modulate NF-κB activity in a dynamic manner, either repressing orenhancing target gene expression. In another hand, Tuberculosis (TB), a majorinfectious disease caused by Mycobacterium tuberculosis (MTB), infects alveolarMf and, hence, promotes a cellular IR, which becomes harmful when prolongedover time, being central to the immunopathology of TB. This work aimed toevaluate the participation of NR4As in the Mf response when they are exposedto MTB antigens. In this regard, we differentiated cells from the THP-1 cell lineinto inflammatory and anti-inflammatory Mf (M1 and M2 respectively) andexposed them to MTB irradiated (MTBi) at different times (1, 3, 6, and 24 H).Then, we assessed the mRNA expression of CD80, NR4A1-3, NFKB1,NFKBIA/B, IL-1β, IL-6, IL-10, HIF1α and Caspase 3. M1 cells showed animportant increase in CD80, NR4A2 and 3, IL1β, HIF1α, and NFKB1, as well asits inhibitors A and B, particularly after 6 H of treatment, with its expression beingeven higher, and IL-10 mRNA augmented, provided MTBi was added to thesecultures. Regarding M2 cells, only NR4A1 and IL-10 were notably expressedbefore MTBi treatment. However, after 1 H of mycobacteria exposure, allanalyzed genes were expressed, particularly the inflammatory ones. On the otherhand, MTBi-treated Mf showed an increase in NR4A1 and 2, IL-1β, IL-10, NFKB1,NFKBIA and NFKBIB expression. These results suggest that MTBi induces aclearly augmented expression in pro-inflammatory genes, together with IL-10mRNA transcripts. The coexistence of inflammatory and anti-inflammatorymediators, along with an increase in NFκB inhibitors may imply an attempt toregulate the strong inflammatory response elicited by the pathogen presence,wherein NR4As are likely to play a regulatory role in this regard.