The Complement Cascade as a Mediator of Human Malignant Hematopoietic Cell Trafficking

Abstract

The complement cascade (ComC) cleavage fragments C3a and C5a regulate the trafficking of normal, differentiated hematopoietic cells, although they do not chemoattract more primitive hematopoietic stem/progenitor cells (HSPCs). By contrast, human myeloid and lymphoid leukemia cell lines and clonogenic blasts from chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML) patients respond to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. Consistent with this finding, C3a and C5a receptors are expressed by leukemic cells at the mRNA (RT-PCR) and protein (FACS) levels, and these cells respond to C3a and C5a stimulation by phosphorylation of p44/42 MAPK and AKT. However, neither of these ComC cleavage fragments have an effect on cell proliferation or survival. In parallel, we found that inducible heme oxygenase 1 (HO-1)–an anti-inflammatory enzyme, is a negative regulator of ComC-mediated trafficking of malignant cells and that stimulation of these cells by C3 or C5 cleavage fragments downregulates HO-1 expression in a p38 MAPK-dependent manner, rendering cells exposed to C3a or C5a more mobile. We propose that, while the ComC is not directly involved in the proliferation of malignant hematopoietic cells, its activation in leukemia/lymphoma patients (e.g., as a result of accompanying infections or sterile inflammation after radio-chemotherapy) enhances the motility of malignant cells and contributes to their dissemination in a p38 MAPK–HO-1 axis-dependent manner. Based on this idea, we propose that inhibition of p38 MAPK or upregulation of HO-1 by available small-molecule modulators would have a beneficial effect on ameliorating expansion and dissemination of leukemia/lymphoma cells in clinical situations in which the ComC becomes activated. Finally, since we detected expression of C3 and C5 mRNA in human leukemic cell lines, further study of the potential role of the complosome in regulating the behavior of these cells is needed.

Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts

“…Moreover, we also observed a decrease in expression of mRNA for the Aim2 inflammasome and selected DAMPs, including high mobility group box 1 (HMGB1) protein and the S100 calcium-binding protein S100a9. Of note, all these molecules are important in activating the complement cascade (ComC), which, as we demonstrated in the past, is important for optimal homing and engraftment of transplanted HSPCs [13,31,32]. In fact, this trend was paralleled by decreased activation of the ComC in the plasma of Nlrp3-KO mice compared with WT control animals, reflected by a lower level of C5a in an ELISA assay (Fig.…”

Monocyte–macrophage polarization and recruitment pathways in the tumour microenvironment of B‐cell acute lymphoblastic leukaemia

“…Literature data indicate that C5a could play a leukaemia‐promoting role by influencing, in concert with C3a, the motility of leukaemia and lymphoma cells by down‐regulating HO‐1 48 . Interestingly, it has also been demonstrated, in the context of colon cancer, 32 that, by binding to its cognate receptors CD88 and GPR77 on macrophages, C5a can contribute, in concert with CCL2, to LAM recruitment to the BM and to their polarization to a tumour‐promoting M2‐like phenotype.…”

Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression

“…Former studies report the establishment of a pro-inflammatory microenvironment in hematopoietic organs through complement activation, following chemotherapy or radiation treatment (reviewed in 51 ). Complement activation promotes tumor growth and oncogenesis 50 .…”