Anaphylatoxin C5a Induces Monocyte Recruitment and Differentiation into Dendritic Cells by TNF-α and Prostaglandin E2-Dependent Mechanisms

Abstract

Although monocytes can be directed to develop into dendritic cells (DC) in vitro, the molecular mechanisms that induce their transformation in vivo are largely unknown. In the present study we employed an in vivo SCID mouse model to investigate the impact of two proinflammatory chemotaxins, the anaphylatoxin C5a and the chemokine macrophage inflammatory protein-1α (CCL3), on the differentiation of human monocytes and immature DC generated from monocytes in the presence of GM-CSF and IL-4. Both C5a and macrophage inflammatory protein-1α recruited human monocytes and immature DC into the peritoneal cavity of SCID mice, but only C5a induced their differentiation into phenotypically mature DC by 48 h after injection. Macrophages derived from monocytes by in vitro culture were resistant to C5a-mediated transformation in vivo. The effect of C5a was indirect, since C5a-stimulated TNF-α and PGE2 were found to be obligatory as well as sufficient to induce differentiation of monocytes. In contrast to monocytes, in vitro generated immature DC required TNF-α, but not PGE2, for their C5a-mediated maturation in vivo. C5a-transformed monocytes represented an inflammatory type of DC, as they constitutively secreted high amounts of TNF-α, but also retained the capacity to release the Th1 cytokine IL-12 p70 upon stimulation with CD40 ligand. In summary, we identified for the first time a cascade of inflammatory signals that can induce the transformation of monocytes into DC in vivo. This novel function emphasizes the important immunoregulatory role of C5a at the interface of innate and adaptive immunity.

Decay Accelerating Factor Can Control T Cell Differentiation into IFN-γ-Producing Effector Cells via Regulating Local C5a-Induced IL-12 Production

“…This result is consistent with C5a-induced up-regulation of IL-12 noted by one group (25) but is contrary to the dose-dependent down-regulatory effects of C5a on LPS-or anti-CD40-induced IL-12 production as described by others (35)(36)(37)(38)(39). To resolve this discrepancy, we compared IL-12 production between LPS-pretreated and control untreated peritoneal macrophages (Fig.…”

Recruitment of a Prostaglandin E Receptor Subtype, EP3-Expressing Bone Marrow Cells Is Crucial in Wound-Induced Angiogenesis

“…76 The chemokine macrophage inflammatory protein-1 promotes the recruitment of monocytes into the peritoneal cavity of mice and their subsequent differentiation into macrophages, and these events are mediated indirectly by PGE 2 . 77 Thus, the present result may reflect an unexplored role of EP3 receptor signaling in response to PGE 2 in the differentiation and migration of mononuclear cells.…”

Differential CD4+ T‐cell memory responses induced by two subsets of human monocyte‐derived dendritic cells

“…Nevertheless, it appears that the equivalent mouse monocyte subsets are precursors for DC in vivo 15,16 and total human monocytes transferred into severe combined immunodeficiency (SCID) mice acquire the phenotypic characteristics of DC. 4 Whether human DC subsets other than 16 -mDC and 16 + mDC have a direct influence on memory responses in vivo is yet to be determined. However, our findings could have practical relevance for clinical approaches.…”

“…2 In vivo, they migrate from blood to inflammatory sites where many differentiate to macrophages, 2 which apparently fail to initiate T-cell responses. 3 Other infiltrating monocytes become DC in the presence of phagocytic or chemoattractant stimuli 2,4 and are able to present antigens and prime naive lymphocytes. 5 In vivo responses of naive T lymphocytes against particulate antigens are mainly dependent on monocyte-derived DC, 6 confirming the biological relevance of these cells.…”