Abstract
Macrophage migration and infiltration is an important first step in many pathophysiological processes, in particular inflammatory diseases. Redox modulation of the migratory signalling processes has been reported in endothelial cells, vascular smooth muscle cells and fibroblasts. However the redox modulation of the migratory process in macrophages and in particular that from the NADPH oxidase-2 (Nox2) dependent ROS has not been established. To investigate the potential role of Nox2 in the migratory response of macrophages, bone marrow derived macrophages were obtained from WT and NOX2 knockout mice (Nox2KO) and subjected to CSF-1 stimulation. We report here that loss of Nox2 expression in BMM resulted in a significant reduction in the CSF-1 induced spreading response suggesting that Nox2 can modulate cytoskeletal events. Moreover, Nox2KO BMMs were deficient in cellular displacement in the presence of CSF-1. More significantly, when challenged with a gradient of CSF-1, Nox2KO BMMs showed a complete loss of chemotaxis accompanied by a reduction in cell migration speed and directional migration persistence. These results point to a specific role for Nox2KO downstream of CSF-1 during the BMM migratory response. Indeed, we have further found that Nox2KO BMMs display a significant reduction in the levels of ERK1/2 phosphorylation following stimulation with CSF-1.Thus Nox2 is important in BMM cellular motion to CSF-1 stimulation and necessary for their directed migration towards a CSF-1 gradient, highlighting Nox2 dependent signalling as a potential anti-inflammatory target.
Highlights
Several isoforms of the gp91phox catalytic subunit of NADPH oxidase have been described
This paper investigates whether the NADPH oxidase-2 (Nox2)-dependent NADPH oxidase modulates the migration of macrophages and in particular to a common tissue chemoattractant, CSF-1
NOX2 knockout mice (Nox2KO) Macrophages have an Increased Spread Area We were interested in establishing whether Nox2 plays a role in the infiltration of macrophages at sites of inflammatory response, such as those that are thought to be associated with tissue repair or conditions such as atherosclerosis
Summary
Several isoforms of the gp91phox catalytic subunit of NADPH oxidase have been described These isoforms are termed NOXs, and comprise Nox, Duox and 2 with Nox being the new name for gp91phox [1]. Superoxide-generating enzymes are a major sources of ROS and have been shown, by way of redox modulation of cellular signalling, to play important roles in disease pathophysiology, in particular inflammatory diseases [2,3,4]. It has been shown that within atherosclerotic plaques, in ApoE2/2 mice, macrophages were a prominent source of Nox2 [5]. Global deletion of Nox in the ApoE2/2 mice inhibited atherosclerotic lesion development in the aortic arch, thoracic and abdominal aorta [5]
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