Induction of the antiviral factors APOBEC3A and RSAD2 upon CCL2 neutralization in primary human macrophages involves NF-κB, JAK/STAT, and gp130 signaling.

Autor:	Covino DA; National Center for Global Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy., Farina I; National Center for Global Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy., Catapano L; National Center for Global Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy., Sozzi S; National Center for Global Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy., Spadaro F; Core Facilities, Microscopy Unit, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy., Cecchetti S; Core Facilities, Microscopy Unit, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy., Purificato C; National Center for Global Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy., Gauzzi MC; National Center for Global Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy., Fantuzzi L; National Center for Global Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
Jazyk:	angličtina
Zdroj:	Journal of leukocyte biology [J Leukoc Biol] 2024 Oct 01; Vol. 116 (4), pp. 876-889.
DOI:	10.1093/jleuko/qiae123
Abstrakt:	The CCL2/CC chemokine receptor 2 axis plays key roles in the pathogenesis of HIV-1 infection. We previously reported that exposure of monocyte-derived macrophages to CCL2 neutralizing antibody (αCCL2 Ab) restricted HIV-1 replication at postentry steps of the viral life cycle. This effect was associated with induction of transcripts coding for innate antiviral proteins, including APOBEC3A and RSAD2. This study aimed at identifying the signaling pathways involved in induction of these factors by CCL2 blocking in monocyte-derived macrophages. Through a combination of pharmacologic inhibition, quantitative reverse transcription polymerase chain reaction, Western blotting, and confocal laser-scanning microscopy, we demonstrated that CCL2 neutralization activates the canonical NF-κB and JAK/STAT pathways, as assessed by time-dependent phosphorylation of IκB, STAT1, and STAT3 and p65 nuclear translocation. Furthermore, pharmacologic inhibition of IκB kinase and JAKs strongly reduced APOBEC3A and RSAD2 transcript accumulation elicited by αCCL2 Ab treatment. Interestingly, exposure of monocyte-derived macrophages to αCCL2 Ab resulted in induction of IL-6 family cytokines, and interference with glycoprotein 130, the common signal-transducing receptor subunit shared by these cytokines, inhibited APOBEC3A and RSAD2 upregulation triggered by CCL2 neutralization. These results provide novel insights into the signal transduction pathways underlying the activation of innate responses triggered by CCL2 neutralization in macrophages. Since this response was found to be associated with protective antiviral effects, the new findings may help design innovative therapeutic approaches targeting CCL2 to strengthen host innate immunity. Competing Interests: Conflict of interest statement. None declared. (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)
Databáze:	MEDLINE
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