Abstract
GM-CSF and IL-3 are hematopoietic cytokines that also modulate the effector functions of several immune cell subsets. In particular, GM-CSF and IL-3 exert a significant control on monocyte and macrophage effector functions, as assessed in experimental models of inflammatory and autoimmune diseases and also in human studies. Here, we sought to investigate the mechanisms and the extent to which GM-CSF and IL-3 modulate the pro-inflammatory, LPS-mediated, activation of human CD14+ monocytes taking into account the new concept of trained immunity (i.e., the priming stimulus modulates the response to subsequent stimuli mainly by inducing chromatin remodeling and increased transcription at relevant genetic loci). We demonstrate that GM-CSF and IL-3 priming enhances TNF-α production upon subsequent LPS stimulation (short-term model of trained immunity) in a p38- and SIRT2-dependent manner without increasing TNF primary transcript levels (a more direct measure of transcription), thus supporting a posttranscriptional regulation of TNF-α in primed monocytes. GM-CSF and IL-3 priming followed by 6 days of resting also results in increased TNF-α production upon LPS stimulation (long-term model of trained immunity). In this case, however, GM-CSF and IL-3 priming induces a c-Myc-dependent monocyte renewal and increase in cell number that is in turn responsible for heightened TNF-α production. Overall, our results provide insights to understand the biology of monocytes in health and disease conditions in which the hematopoietic cytokines GM-CSF and IL-3 play a role and also extend our knowledge of the cellular and molecular mechanisms of trained immunity.
Highlights
GM-CSF and IL-3 are hematopoietic cytokines that bind to heterodimeric receptors composed of a β common subunit (CD131) and specific α subunits (CD116 and CD123, respectively) [1, 2]
In order to evaluate the effect of GM-CSF and IL-3 on the pro-inflammatory LPS-mediated activation of human CD14+ monocytes, we simultaneously treated these cells with LPS and GM-CSF or IL-3 and assessed the production of TNF-α, IL-1β, and IL-6
In accordance with the results obtained with β-glucan, cells primed with GM-CSF or IL-3 secreted higher levels of TNF-α compared to those primed with M-CSF and LPS (Figure 5B). These results could suggest stable chromatin remodeling events in response to GM-CSF and IL-3 priming, we found that GM-CSF and IL-3 priming increased total cellular protein content (Figure 5C) and that monocytes primed with GM-CSF, IL-3, and M-CSF expressed comparable levels of TNF RNA upon LPS stimulation (Figure 5D)
Summary
GM-CSF and IL-3 are hematopoietic cytokines that bind to heterodimeric receptors composed of a β common subunit (CD131) and specific α subunits (CD116 and CD123, respectively) [1, 2] These cytokines are produced by many immune and non-immune cells and are important mediators of emergency myelopoiesis, albeit their role in steady-state myelopoiesis is dispensable. GM-CSF and IL-3 modulate the effector functions of several mature immune cell subsets and have been shown to play a role in inflammatory and autoimmune diseases [7,8,9,10,11]. GM-CSF promotes the maturation and effector functions of myeloid cells (e.g., monocytes and neutrophils) and plays a protective role in an experimental model of acute sepsis [12]. The mechanisms and the extent to which GM-CSF and IL-3 modulate the proinflammatory (e.g., LPS-mediated) activation of human CD14+ monocytes are still unclear
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