Dual oxidase 1 limits the IFNγ-associated antitumor effect of macrophages

Abstract

BackgroundMacrophages play pivotal roles in tumor progression and the response to anticancer therapies, including radiotherapy (RT). Dual oxidase (DUOX) 1 is a transmembrane enzyme that plays a critical role in oxidant generation.MethodsSince we found DUOX1 expression in macrophages from human lung samples exposed to ionizing radiation, we aimed to assess the involvement of DUOX1 in macrophage activation and the role of these macrophages in tumor development.ResultsUsing Duox1−/− mice, we demonstrated that the lack of DUOX1 in proinflammatory macrophages improved the antitumor effect of these cells. Furthermore, intratumoral injection of Duox1−/− proinflammatory macrophages significantly enhanced the antitumor effect of RT. Mechanistically, DUOX1 deficiency increased the production of proinflammatory cytokines (IFNγ, CXCL9, CCL3 and TNFα) by activated macrophages in vitro and the expression of major histocompatibility complex class II in the membranes of macrophages. We also demonstrated that DUOX1 was involved in the phagocytotic function of macrophages in vitro and in vivo. The antitumor effect of Duox1−/− macrophages was associated with a significant increase in IFNγ production by both lymphoid and myeloid immune cells.ConclusionsOur data indicate that DUOX1 is a new target for macrophage reprogramming and suggest that DUOX1 inhibition in macrophages combined with RT is a new therapeutic strategy for the management of cancers.

Protective effects of cannabidiol on the membrane proteins of skin keratinocytes exposed to hydrogen peroxide via participation in the proteostasis network

“…It is possible that the potential inhibition of NADH-ubiquinone oxidoreductase protects cells from damage associated with excessive generation of ROS, but may also attenuate beneficial oxidative signaling [ 90 ]. However, it is known, that dual oxidase 1 deficiency can also induce the release of pro-inflammatory cytokines such as IFNγ and TNFα [ 91 ]. The above suggestions are confirmed by studies of other authors, which have shown that the formation of 4-ONE-protein adducts is associated with the inhibition of pyruvate kinase and hsp90 [ 69 ] and high-density lipoproteins dysfunction [ 24 ].…”

Pan-Cancer Analysis Shows TP53 Mutations Modulate the Association of NOX4 with Genetic Programs of Cancer Progression and Clinical Outcome

“…We discovered a striking association between NOX2 and macrophage signatures that strongly suggests that the major source of NOX2 is derived from TAMs ( Figure 5 ). Although NOX2 is considered the primary source of ROS in macrophages, recent studies revealed that other less abundant NOX enzymes can affect the fate and function of macrophages, including DUOX1, NOX1 and NOX4 [ 42 , 43 , 44 ]. For example, studies with Nox1/Nox2 double-knockout mice suggest both oxidases support monocyte differentiation into macrophages [ 43 ].…”

Ferroptosis-Related Gene Signature and Patterns of Immune Infiltration Predict the Overall Survival in Patients With Lung Adenocarcinoma

“…Inflammation associated with monocyte/macrophage cells was promoted by ANGPTL7 through the mitogen-activated protein kinase (MAPK) signaling pathway (Qian et al, 2016). Dual oxidase (DUOX) 1, a transmembrane enzyme, plays a critical role in limiting macrophage antitumor activity (Meziani et al, 2020).…”