Participation of nuclear receptors nr4a in the immune response during tuberculosis

FERREIRA LEMES S; ARMANDO M; DERIO M; BOTTASSO O; PEREZ A; SANTUCCI N

San Luis

Congreso; LXXI Reunión Anual de la Sociedad Argentina de Inmunología; 2023

Sociedad Argentina de Inmunología

Nuclear receptors (NRs) are a superfamily of ligand-dependent transcription factors that bind to numerous kinds of molecules, mostly hydrophobics, and with an important role in the immune endocrine regulation of homeostasis and pathophysiology. Within the NRs, NR4As orphan receptors have emerged as important regulators of immune cell polarization in immune response (IR) and inflammation, particularly affecting NF-κB signalling. In macrophages (Mf) NR4A receptors modulate NF-κB activity in a dynamic manner, either repressing or enhancing target gene expression. In another hand, Tuberculosis (TB), a major infectious disease caused by Mycobacterium tuberculosis (MTB), infects alveolar Mf and, hence, promotes a cellular IR, which becomes harmful when prolonged over time, being central to the immunopathology of TB. This work aimed to evaluate the participation of NR4As in the Mf response when they are exposed to MTB antigens. In this regard, we differentiated cells from the THP-1 cell line into inflammatory and anti-inflammatory Mf (M1 and M2 respectively) and exposed them to MTB irradiated (MTBi) at different times (1, 3, 6, and 24 H). Then, we assessed the RNAm expression of CD80, NR4A1-3, NFKB1, NFKBIA/B, IL-1β, IL-6, IL-10, HIF1α and Caspase 3. M1 cells showed an important increase in CD80, NR4A2 and 3, IL1β, HIF1α, and NFKB1, as well as its inhibitors A and B, particularly after 6 H of treatment, with its expression being even higher provided MTBi was added to these cultures. We also found IL-10 RNAm was augmented. Regarding M2 cells, only NR4A1 and IL-10 were notably expressed before MTBi treatment. However, after 1 H of mycobacteria exposure, all analyzed genes were expressed, particularly the inflammatory ones. On the other hand, 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 a clearly augmented expression in pro-inflammatory genes, together with IL-10 RNAm transcripts. The coexistence of inflammatory and anti-inflammatory mediators, along with an increase in NFκB inhibitors may imply an attempt to regulate the strong inflammatory response elicited by the pathogen presence, wherein NR4As are likely to play a regulatory role in this regard.