Attenuated Negative Feedback in Monocyte-Derived Macrophages From Persons Living With HIV: A Role for IKAROS

• Published in: Frontiers in immunology 2021-11, Vol.12, p.785905-785905
• Main Authors: Faia, Celeste, Plaisance-Bonstaff, Karlie, Vittori, Cecilia, Wyczechowska, Dorota, Lassak, Adam, Meyaski-Schluter, Mary, Reiss, Krzysztof, Peruzzi, Francesca
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - administration & dosage; Case-Control Studies; Cytokines - metabolism; Disease Susceptibility - immunology; endotoxin tolerance; Feedback, Physiological; Female; Gene Expression Regulation - immunology; Healthy Volunteers; HIV - immunology; HIV - isolation & purification; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; HIV-1; Humans; Ikaros; Ikaros Transcription Factor - metabolism; immune dysfunction; Immunology; Inflammation - blood; Inflammation - immunology; Lipopolysaccharides - immunology; Macrophages - immunology; Macrophages - metabolism; Male; Middle Aged; monocytes; Signal Transduction - drug effects; Signal Transduction - immunology; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Viral Load - drug effects; Viral Load - immunology
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.785905

Persons living with HIV (PLWH) are at higher risk of developing secondary illnesses than their uninfected counterparts, suggestive of a dysfunctional immune system in these individuals. Upon exposure to pathogens, monocytes undergo epigenetic remodeling that results in either a trained or a tolerant phenotype, characterized by hyper-responsiveness or hypo-responsiveness to secondary stimuli, respectively. We utilized CD14 monocytes from virally suppressed PLWH and healthy controls for analysis following polarization of these cells toward a pro-inflammatory monocyte-derived macrophage (MDM) phenotype. We found that in PLWH-derived MDMs, pro-inflammatory signals ( , , , miR-155-5p, and ) dominate over negative feedback signals ( , , , , and miR-146a-5p), favoring an abnormally trained phenotype. The mechanism of this reduction in negative feedback involves the attenuated expression of IKZF1, a transcription factor required for synthesis of RELA during LPS-induced inflammatory responses. Furthermore, restoring IKZF1 expression in PLWH-MDMs partially reinstated expression of negative regulators of inflammation and lowered the expression of pro-inflammatory cytokines. Overall, this mechanism may provide a link between dysfunctional immune responses and susceptibility to co-morbidities in PLWH with low or undetectable viral load.