Abstract
BackgroundNumerous tissue-derived factors have been postulated to be involved in tissue migration of circulating monocytes. The aim of this study was to evaluate whether a defined hypoxic gradient can induce directed migration of naïve human monocytes and to identify responsible autocrine/paracrine factors.MethodsMonocytes were isolated from peripheral blood mononuclear cells, transferred into chemotaxis chambers and subjected to a defined oxygen gradient with or without the addition of CCL26. Cell migration was recorded and secretome analyses were performed.ResultsCell migration recordings revealed directed migration of monocytes towards the source of hypoxia. Analysis of the monocyte secretome demonstrated a reduced secretion of 70% (19/27) of the analyzed cytokines under hypoxic conditions. The most down-regulated factors were CCL26 (− 99%), CCL1 (− 95%), CX3CL1 (− 95%), CCL17 (− 85%) and XCL1 (− 83%). Administration of recombinant CCL26 abolished the hypoxia-induced directed migration of human monocytes, while the addition of CCL26 under normoxic conditions resulted in a repulsion of monocytes from the source of CCL26.ConclusionsHypoxia induces directed migration of human monocytes in-vitro. Autocrine/paracrine released CCL26 is involved in the hypoxia-mediated monocyte migration and may represent a target molecule for the modulation of monocyte migration in-vivo.
Highlights
Peripheral blood monocytes representing about 4–8% of all circulating leukocytes, possess only a limited life span in the blood circulation and undergo spontaneous apoptosis after 24–48 h [1]
Employing an enzymatic hypoxia model in combination with chemotaxis chambers stable oxygen gradients are obtained The induction of oxygen gradients was performed by employing commercially available chemotaxis chambers (Ibidi) in combination with our recently described enzymatic hypoxia model [14, 15]
Concerning the temporal component of hypoxia, measurements showed a rapid formation of oxygen gradients within the migration chamber
Summary
Peripheral blood monocytes representing about 4–8% of all circulating leukocytes, possess only a limited life span in the blood circulation and undergo spontaneous apoptosis after 24–48 h [1]. Additional monocytes may migrate along a specific chemotactic gradient and accumulate within the hypoxic areas of the affected tissues [3]. The infiltration of monocytes and the release of inflammatory mediators both amplify the pro-inflammatory immune response and can lead to an expansion of the initial tissue injury [8]. A number of tissue derived factors, such as chemokines, complement factors as well as products of tissue matrix degradation have been postulated to be responsible for the directed migration of monocytes during inflammatory processes [4]. Numerous tissue-derived factors have been postulated to be involved in tissue migration of circulating monocytes. The aim of this study was to evaluate whether a defined hypoxic gradient can induce directed migration of naïve human monocytes and to identify responsible autocrine/paracrine factors
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