IL‐3 synergises with basophil‐derived IL‐4 and IL‐13 to promote the alternative activation of human monocytes

Abstract

Basophil-derived IL-4 is involved in the alternative activation of mouse monocytes, as recently shown in vivo. Whether this applies to human basophils and monocytes has not been established yet. Here, we sought to characterize the interaction between basophils and monocytes and identify the molecular determinants. A basophil-monocyte co-culture model revealed that IL-3 and basophil-derived IL-4 and IL-13 induced monocyte production of CCL17, a marker of alternative activation. Critically, IL-3 and IL-4 acted directly on monocytes to induce CCL17 production through histone H3 acetylation, but did not increase the recruitment of STAT5 or STAT6. Although freshly isolated monocytes did not express the IL-3 receptor α chain (CD123), and did not respond to IL-3 (as assessed by STAT5 phosphorylation), the overnight incubation with IL-4 (especially if associated with IL-3) upregulated CD123 expression. IL-3-activated JAK2-STAT5 pathway inhibitors reduced the CCL17 production in response to IL-3 and IL-4, but not to IL-4 alone. Interestingly, monocytes isolated from allergen-sensitized asthmatic patients exhibited a higher expression of CD123. Taken together, our data show that the JAK2-STAT5 pathway modulates both basophil and monocyte effector responses. The coordinated activation of STAT5 and STAT6 may have a major impact on monocyte alternative activation in vitro and in vivo.

Basophil Recruitment into Tumor-Draining Lymph Nodes Correlates with Th2 Inflammation and Reduced Survival in Pancreatic Cancer Patients

“…Preliminary data do not support a role for TSLP in driving CCL7/MCP3 secretion by M2 monocytes; thus, future investigation would possibly identify the CAFs-derived factor(s) implicated. In addition, it has been shown that IL3 synergizes with basophil-derived IL4 and IL13 to promote M2 differentiation (47) and that activated basophils can secrete IL3 (48). It is possible that once the mechanisms of basophil recruitment and activation have been established, basophilderived IL4 and IL3 contribute to reinforce both basophil activation through an autocrine loop and the M2 polarization in TDLNs.…”

GM-CSF and IL-3 Modulate Human Monocyte TNF-α Production and Renewal in In Vitro Models of Trained Immunity

“…Although we found similarities as well as differences between GM-CSF and IL-3 priming in the pathways required for monocyte renewal, it is noteworthy that GM-CSF priming induces a greater monocyte expansion than IL-3 priming. The reason for this difference probably relies in the constitutive expression of CD116 (the α subunit of GM-CSF receptor) by human monocytes (58), while CD123 (the α subunit of IL-3 receptor) expression is inducible (16, 59). Nevertheless, bone marrow CD14 + monocytes express CD123 (60), thus it is tempting to speculate that IL-3 preferentially acts on bone marrow-resident monocytes, while GM-CSF exerts its effect on peripheral blood monocytes.…”

“…Interestingly, GM-CSF modulates several functions of human CD14 + monocytes (13–15), including cytokine production upon LPS stimulation. We have recently shown that GM-CSF and IL-3 synergize with IL-4 to enhance the production of the IL-4-responsive chemokine CCL17/TARC by human CD14 + monocytes (16). Thus, GM-CSF and IL-3 exert a significant control on monocyte effector functions.…”

Activation of Human Basophils by A549 Lung Epithelial Cells Reveals a Novel IgE-Dependent Response Independent of Allergen

“…In fact, several studies have shown that basophils, by producing IL-4, facilitate the pro-Th2 activities of other immune cells, including T cells (4), B cells (5), monocytes (6, 7), eosinophils (8) and, most recently, innate lymphoid cells type 2 (ILC2) (9). …”