Splenic Innate B1 B Cell Plasmablasts Produce Sustained Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-3 Cytokines during Murine Malaria Infections

Abstract

The physiopathology of malaria, one of the most deadly human parasitic diseases worldwide, is complex, as it is a systemic disease involving multiple parasitic stages and hosts and leads to the activation of numerous immune cells and release of inflammatory mediators. While some cytokines increased in the blood of patients infected with Plasmodium falciparum have been extensively studied, others, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), have not received much attention. GM-CSF and IL-3 belong to the β common (βc/CD131) chain family of cytokines, which exhibit pleiotropic functions, including the regulation of myeloid cell growth, differentiation, and activation. GM-CSF can be secreted by multiple cell types, whereas IL-3 is mostly restricted to T cells, yet innate response activator (IRA) B cells, a subset of innate B1 B cells, also produce significant amounts of these cytokines during bacterial sepsis via Toll-like receptor 4 (TLR4)/MyD88 sensing of lipopolysaccharides. Herein, using murine models of malaria, we report a sustained production of GM-CSF and IL-3 from IgM+ and IgM−/IgG+ CD138+ Blimp-1+ innate B1b B cell plasmablasts. IgM+ B1b B cells include IRA-like and non-IRA B cells and express higher levels of both cytokines than do their IgG+ counterparts. Interestingly, as infection progresses, the relative proportion of IgM+ B1 B cells decreases while that of IgG+ plasmablasts increases, correlating with potential isotype switching of GM-CSF- and IL-3-producing IgM+ B1 B cells. GM-CSF/IL-3+ B1 B cells originate in the spleen of infected mice and are partially dependent on type I and type II interferon signaling to produce both cytokines. These data reveal that GM-CSF and IL-3 are produced during malaria infections, initially from IgM+ and then from IgG+ B1b B cell plasmablasts, which may represent important emergency cellular sources of these cytokines. These results further highlight the phenotypic heterogeneity of innate B1 B cell subsets and of their possible fates in a relevant murine model of parasitic infection in vivo.

Malaria Pigment Hemozoin Impairs GM-CSF Receptor Expression and Function by 4-Hydroxynonenal

“…The introduction of 4-HNE adducts in the nascent protein chain during translation and export may also impact on CD 116 export to the membrane, thus resulting in decreased expression and enhanced degradation, a commonly observed event for 4-HNE tagged proteins [ 55 ]. GM-CSF has been reported to increase during malaria infection [ 56 , 57 ]. The cytokine is essential for differentiation of hematopoietic stem cells to erythrocytes, neutrophils, monocytes, eosinophils, and megakaryocytes [ 58 ] and its priming activity on terminally differentiated myeloid cells is well recognised [ 58 , 59 ] and the rationale for inclusion of one plasmid DNA encoding human GM-CSF in a multivalent DNA malaria vaccine [ 60 ].…”

Single-cell transcriptome profiling and the use of AID deficient mice reveal that B cell activation combined with antibody class switch recombination and somatic hypermutation do not benefit the control of experimental trypanosomosis

“…As TLR/MyD88 signaling gives rise to VSG-specific antibody induction [56], and TLR signaling appears crucial for maintenance of B cell memory [57,58], CpG DNA has even been proposed as an adjuvant in anti-trypanosome vaccine approaches [59][60][61][62]. Finally, it is worth nothing that IgM + B1 B cells have also been shown to play an important role in malaria-associated antibody production [63] as well as M. tuberculosis associated IgM secretion [64].…”

X-linked immunodeficient (XID) mice exhibit high susceptibility to Cryptococcus gattii infection

“…Showing that the malfunction of determinants of the immune system corroborate for a higher mortality and susceptibility to cryptococcosis 64 . Therefore, the absence of the B-1 cell component in the XID mice characterizes the loss of cells that are very important for infection resolution 24 , 25 , 38 , 65 , which justify the worsening of the clinical score that has been observed previously using C. neoforomans 66 , and now with C. gattii . We also found that the XID animals still had an extremely deficient serum level of IgM and IgG anti-GXM antibodies, suggesting that antibodies play an important role in infection and act by limiting the spread of yeast.…”