Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Flores-Fernández, Rocio; Aponte-López, Angélica; Suárez-Arriaga, Mayra C.; Gorocica-Rosete, Patricia; Pizaña-Venegas, Alberto; Chávez-Sanchéz, Luis; Blanco-Favela, F; Fuentes‐Pananá, Ezequiel M.; Chávez-Rueda, Adriana Karina

doi:10.3390/cells10020316

Cited by 10 publications

(14 citation statements)

References 56 publications

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“…Thus, we interpretate these data as PRL may not increase the B-GC cell differentiation, but that it may promote an alternative mechanism to increase the number of differentiating B-GCs. PRL can increase the survival of immature B cells in MRL/lpr mice ( 20 ). However, we did not observe an increased survival of PRL-treated B-GCs in the culture conditions ( Figure 3K ).…”

Section: Resultsmentioning

confidence: 99%

“…PRL is a multifunctional hormone that is essential for the survival and proliferation of different cell types, both immune and nonimmune ( 44 , 45 ). PRL regulates apoptosis by increasing the expression of antiapoptotic genes in both T cells ( 46 ), and immature B cells ( 20 ). Although in immature B cells from MRL/lpr mice, PRL can increase the survival and protect against apoptosis, it did not have this effect on already differentiated mature B cells (B-GCs), even though both cells express the long isoform of the receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Although in immature B cells from MRL/lpr mice, PRL can increase the survival and protect against apoptosis, it did not have this effect on already differentiated mature B cells (B-GCs), even though both cells express the long isoform of the receptor. This difference may be due to differential signaling pathway activation mediated by PRL at each stage of B-cell maturation, while in immature B cells, it seems to preferentially activate STAT3 ( 20 ). We observed here that it preferentially activates STAT1 in B-GC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Our group has reported that the different stages of maturation of B cells in bone marrow (proB, preB, and immature) ( 15 ), and in the spleen (transitional, follicular [FO] and marginal zone [MZ]) express the PRL receptor ( 16 ), both in strains that do not develop SLE (C57BL/6) and in models affected by the disease (MRL/lpr). In addition, we identified that PRL influences the B-cell maturation process by rescuing immature autoreactive B cells from apoptosis ( 20 , 21 ). However, the mechanism by which PRL may favor autoantibody production is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Prolactin promotes proliferation of germinal center B cells, formation of plasma cells, and elevated levels of IgG3 anti-dsDNA autoantibodies

et al. 2022

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Systemic lupus erythematosus (SLE) mainly affects females at reproductive age, which has been associated with hormones, such as prolactin (PRL). Different studies suggest that PRL exacerbates the clinical manifestations of SLE both in patients and in mouse models (e.g., the MRL/lpr strain), increasing the production of autoantibodies, which can be deposited as immune complexes and trigger inflammation and damage to different tissues. The objective of this work was to explore the potential mechanisms by which PRL increases the concentration of self-reactive antibodies in the MRL/lpr SLE model. To this end, we determined the role of PRL on the activation and proliferation of germinal center B cells (B-GCs) and their differentiation into antibody-secreting cells (ASCs). We show that the absolute number and percentage of B-GCs were significantly increased by PRL in vivo or upon in vitro treatment with anti-IgM and anti-CD40 antibodies and PRL. The augmented B-GC numbers correlated with enhanced proliferation, but we did not observe enhanced expression of CD80 and CD86 activation markers or the BCL6 transcription factor, arguing against a more effective differentiation. Nevertheless, we observed enhanced phosphorylation of STAT1, secretion of IL-6, expression of IRF4, numbers of ASCs, and levels of IgG3 antibodies directed against dsDNA. Altogether, these results support the hypothesis that a PRL-mediated expansion of B-GCs yields more self-reactive ASCs, potentially explaining the pathogenic immune complexes that steadily lead to tissue damage during SLE.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prolactin promotes proliferation of germinal center B cells, formation of plasma cells, and elevated levels of IgG3 anti-dsDNA autoantibodies

et al. 2022

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“…Through these mechanisms, PRL participates in the onset of SLE by rescuing cells destined for clonal deletion. The activation of PRLR could also affect clones of immature autoreactive B cells through STAT3 activation and the transcriptional regulation of apoptosis resistance-related genes in an animal SLE model ( 73 ). This decreased apoptosis may be due to the upregulation of anti-apoptotic BCL-XL gene and a concomitant decrease of Bad expression caused by PRL in the MRL/lpr model ( 74 ).…”

Section: Prolactin and Sle: Adaptive Immune Response Cellsmentioning

confidence: 99%

The effect of prolactin on immune cell subsets involved in SLE pathogenesis

et al. 2022

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The higher frequency of autoimmune diseases in the female population compared to males suggests that certain hormones, such as prolactin (PRL), play a role in determining the prevalence of autoimmunity in women, particularly during childbearing age. PRL can act not only as a hormone but also as a cytokine, being able to modulate immune responses. Hyperprolactinemia has been implicated in the pathogenesis of various autoimmune diseases where it may affect disease activity. One of the conditions where PRL has such a role is systemic lupus erythematosus (SLE). PRL regulates the proliferation and survival of both lymphoid and myeloid cells. It also affects the selection of T-cell repertoires by influencing the thymic microenvironment. In autoimmune conditions, PRL interferes with the activity of regulatory T cells. It also influences B cell tolerance by lowering the activation threshold of anergic B cells. The production of CD40L and cytokines, such as interleukin IL-6, are also promoted by PRL. This, in turn, leads to the production of autoantibodies, one of the hallmarks of SLE. PRL increases the cytotoxic activity of T lymphocytes and the secretion of proinflammatory cytokines. The production of proinflammatory cytokines, particularly those belonging to the type 1 interferon (IFN) family, is part of the SLE characteristic genetic signature. PRL also participates in the maturation and differentiation of dendritic cells, promoting the presentation of autoantigens and high IFNα secretion. It also affects neutrophil function and the production of neutrophil traps. Macrophages and dendritic cells can also be affected by PRL, linking this molecule to the abnormal behavior of both innate and adaptive immune responses.This review aimed to highlight the importance of PRL and its actions on the cells of innate and adaptive immune responses. Additionally, by elucidating the role of PRL in SLE etiopathogenesis, this work will contribute to a better understanding of the factors involved in SLE development and regulation.

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Multifunctional cytokine production marks influenza A virus‐specific CD4 T cells with high expression of survival molecules

et al. 2023

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Cytokine production by memory T cells is a key mechanism of T cell mediated protection. However, we have limited understanding of the persistence of cytokine producing T cells during memory cell maintenance and secondary responses. We interrogated antigen‐specific CD4 T cells using a mouse influenza A virus infection model. Although CD4 T cells detected using MHCII tetramers declined in lymphoid and non‐lymphoid organs, we found similar numbers of cytokine+ CD4 T cells at days 9 and 30 in the lymphoid organs. CD4 T cells with the capacity to produce cytokines expressed higher levels of pro‐survival molecules, CD127 and Bcl2, than non‐cytokine+ cells. Transcriptomic analysis revealed a heterogeneous population of memory CD4 T cells with three clusters of cytokine+ cells. These clusters match flow cytometry data and reveal an enhanced survival signature in cells capable of producing multiple cytokines. Following re‐infection, multifunctional T cells expressed low levels of the proliferation marker, Ki67, whereas cells that only produce the anti‐viral cytokine, interferon‐γ, were more likely to be Ki67+. Despite this, multifunctional memory T cells formed a substantial fraction of the secondary memory pool. Together these data indicate that survival rather than proliferation may dictate which populations persist within the memory pool.

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Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Cited by 10 publications

References 56 publications

Prolactin promotes proliferation of germinal center B cells, formation of plasma cells, and elevated levels of IgG3 anti-dsDNA autoantibodies

Prolactin promotes proliferation of germinal center B cells, formation of plasma cells, and elevated levels of IgG3 anti-dsDNA autoantibodies

The effect of prolactin on immune cell subsets involved in SLE pathogenesis

Multifunctional cytokine production marks influenza A virus‐specific CD4 T cells with high expression of survival molecules

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