Extracellular nicotinamide phosphoribosyltransferase boosts IFNγ-induced macrophage polarization independently of TLR4

Giorgia Colombo; Cristina Travelli; Chiara Porta; Armando A Genazzani

doi:10.1016/j.isci.2022.104147

Extracellular nicotinamide phosphoribosyltransferase boosts IFNγ-induced macrophage polarization independently of TLR4

iScience. 2022 Mar 23;25(4):104147. doi: 10.1016/j.isci.2022.104147. eCollection 2022 Apr 15.

Authors

Giorgia Colombo¹, Cristina Travelli², Chiara Porta^{1

3}, Armando A Genazzani¹

Affiliations

¹ Department of Pharmaceutical Sciences, University of Eastern Piedmont, A. Avogadro, 28100 Novara, Italy.
² Department of Drug Sciences, Università degli Studi di Pavia, 27100 Pavia, Italy.
³ Center for Translational Research on Autoimmune & Allergic Diseases (CAAD), Università del Piemonte Orientale, 28100 Novara, Italy.

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT), alongside being a crucial enzyme in NAD synthesis, has been shown to be a secreted protein (eNAMPT), whose levels are increased in patients affected by immune-mediated disorders. Accordingly, preclinical studies have highlighted that eNAMPT participates in the pathogenesis of several inflammatory diseases. Herein, we analyzed the effects of eNAMPT on macrophage-driven inflammation. RNAseq analysis of peritoneal macrophages (PECs) demonstrates that eNAMPT triggers an M1-skewed transcriptional program, and this effect is not dependent on the enzymatic activity. Noteworthy, both in PECs and in human monocyte-derived macrophages, eNAMPT selectively boosts IFNγ-driven transcriptional activation via STAT1/3 phosphorylation. Importantly, the secretion of eNAMPT promotes the chemotactic recruitment of myeloid cells, therefore providing a potential positive feedback loop to foster inflammation. Last, we report that these events are independent of the activation of TLR4, the only eNAMPT receptor that has hitherto been recognized, prompting the knowledge that other receptors are involved.

Keywords: Biological sciences; Immunology; Transcriptomics.