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Effects of IL-10+ B cells/plasma cells on myeloid differentiation in vitro. Primary bone marrow monocytes were stimulated with M-CSF and RANKL and cultured with or without addition of in vitro activated B cells/plasma cells, IL-10R blocking antibodies and control antibodies, as indicated. Three days later, CD115+ monocytes, F4/80+ macrophages, and CD11c+ cells were quantified by flow cytometry. (A) Representative FACS plots (upper panel) and statistical analysis (lower panels) of frequencies and absolute numbers of F4/80+ and CD115+/F4/80− cells are shown. Pooled data from four independent experiments are shown (n = 3 per experiment). (B) Frequencies of CD11c+ cells. Each dot represents the result from one well. Pooled data from two independent experiments are shown (n = 3 per experiment). Statistics: one-way ANOVA. **P < 0.01, ***P < 0.001 and ****P < 0.001.
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Bone marrow plasma cells have been reported to represent a major source of IL-10; however, the impact of plasma cell derived IL-10 in that tissue remains poorly understood. We confirm in this study that even in the absence of acute immune reactions, mature plasma cells represent the dominant IL-10+ cell population in the bone marrow, and identify m...
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Citations
... This underscores the potential of bmDCs to interpret and induce hematopoietic bias in response to immune stimuli. Considering the inherent challenges associated with G-CSF administration, such as the need for repeated injections and symptoms like bone pain, nausea, headache, and fatigue [70], the administration of in Long-lived plasma cells, identified as CD19 − /B220 − / MCH II lo CD138 + in mouse bone marrow, represent a substantial local source of IL-10 under steady-state conditions [97,98]. IL-10 assumes a pivotal role in regulating the proliferation and differentiation of myeloid cells, DCs, and macrophages within the bone marrow, operating in a nonredundant capacity [98,99]. ...
... Considering the inherent challenges associated with G-CSF administration, such as the need for repeated injections and symptoms like bone pain, nausea, headache, and fatigue [70], the administration of in Long-lived plasma cells, identified as CD19 − /B220 − / MCH II lo CD138 + in mouse bone marrow, represent a substantial local source of IL-10 under steady-state conditions [97,98]. IL-10 assumes a pivotal role in regulating the proliferation and differentiation of myeloid cells, DCs, and macrophages within the bone marrow, operating in a nonredundant capacity [98,99]. Myeloid-biased hematopoiesis increases in aged mice and the elderly [100], a phenomenon attributed to the age-related accumulation of plasma cells in the bone marrow. ...
... Diverging from the conventional independent differentiation pathway observed in regulatory T cells, Breg cell differentiation is contingent upon the immune environment in which they operate. Notably, flow cytometry analyses have revealed that under steadystate conditions, IL-10-producing cells constitute 0.1-0.2% of bone marrow cells, with 65% arising from plasma cells and 5% from B cells [98]. Consequently, Breg cells can emerge at different stages of B cell maturation, encompassing immature and mature B cell populations, accounting for the variable immunophenotypes observed in both murine and human contexts [111,112]. ...
Certain immune cells, including neutrophils, macrophages, dendritic cells, B cells, Breg cells, CD4⁺ T cells, CD8⁺ T cells, and Treg cells, establish enduring residency within the bone marrow. Their distinctive interactions with hematopoiesis and the bone marrow microenvironment are becoming increasingly recognized alongside their multifaceted immune functions. These cells play a dual role in shaping hematopoiesis. They directly influence the quiescence, self-renewal, and multi-lineage differentiation of hematopoietic stem and progenitor cells through either direct cell-to-cell interactions or the secretion of various factors known for their immunological functions. Additionally, they actively engage with the cellular constituents of the bone marrow niche, particularly mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts, to promote their survival and contribute to tissue repair, thereby fostering a supportive environment for hematopoietic stem and progenitor cells. Importantly, these bone marrow immune cells function synergistically, both locally and functionally, rather than in isolation. In summary, immune cells residing in the bone marrow are pivotal components of a sophisticated network of regulating hematopoiesis.
... Pro-inflammatory cytokines including interleukin (IL)-1β, IL-2, IL-6, as well as interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α), initiate and amplify the early-phase inflammatory events (Kany et al. 2019). Antiinflammatory cytokines such as IL-10 limit the effects of the pro-inflammatory agents and modulate the inflammatory processes (Meng et al. 2019). Regardless of the trigger stimulus, inflammation induces vasodilation, increases blood flow to the affected area, stimulates the release of further soluble factors that amplify the response, and increases blood vessel permeability, resulting in tissue swelling (Gusev and Zhuravleva 2022). ...
Based on their high antioxidant capacity and noteworthy phytochemistry, Terminalia ferdinandiana fruit and leaves have attracted considerable recent interest for their therapeutic potential. Whilst those studies have reported a variety of therapeutic properties for the fruit, the anti-inflammatory potential of T. ferdinandiana has been largely neglected and the leaves have been almost completely ignored. This study investigated the immune-modulatory and anti-inflammatory properties of T. ferdinandiana fruit and leaf extracts by evaluating their inhibition of multiple pro- and anti-inflammatory cytokines and chemokines secretion in lipopolysaccharide (LPS)-stimulated and unstimulated RAW 264.7 macrophages using multiplex bead immunoassays and ELISA assays. The methanolic extracts were particularly good immune-modulators, significantly inhibiting the secretion of all the cytokines and chemokines tested. Indeed, the methanolic extracts completely inhibited IL-10, IFN-γ, IL-1β, IL-6, MCP-1, and MIP-2a secretion, and almost completely inhibited the secretion of TNF-α. In addition, the methanolic T. ferdinandiana extracts also significantly inhibited cytosolic COX-2 levels (by 87–95%) and the synthesis of the PGE2 (by ~ 98%). In contrast, the methanolic extracts stimulated LTB4 secretion by ~ 60–90%, whilst the aqueous extracts significantly inhibited LTB4 secretion (by ~ 27% each). Exposure of RAW 264.7 cells to the methanolic T. ferdinandiana extracts also significantly down-regulated the cytosolic levels of NF-κB by 33–44%, indicating that the immune-modulatory and anti-inflammatory properties of the extracts may be regulated via a decrease in NF-κB transcription pathways. Taken together, these results demonstrate potent anti-inflammatory properties for the extracts and provide insights into their anti-inflammatory mechanisms.
... However, the ability of these cells to impact the immune response can also be mediated through direct cellular interactions (16). Further extending the sphere of ASC influence, these cells have been shown to regulate aspects of bone marrow (BM) hematopoiesis in both humans (17) and mice (18,19). As hematopoiesis is a continual and life-long process, these studies have shed light on the critical importance of ASCs in every-day homeostatic functions. ...
Antibody-secreting cells are essential contributors to the humoral response. This is due to multiple factors which include: 1) the ability to secrete thousands of antibodies per second, 2) the ability to regulate the immune response and 3) the potential to be long-lived. Not surprisingly, these cells can be found in numerous sites within the body which include organs that directly interface with potential pathogens (e.g., gut) and others that provide long-term survival niches (e.g., bone marrow). Even though antibody-secreting cells were first identified in the thymus of both humans and rodents in the 1960s, if not earlier, only recently has this population begun to be extensively investigated. In this article, we provide an update regarding the current breath of knowledge pertaining to thymus antibody-secreting cells and discuss the potential roles of these cells and their impact on health.
... Moreover, PCs may indirectly increase cytokine levels, supporting their own survival through interaction with other immune cells: as specified above, they could induce IL-6 in DCs via CD28/CD80/CD86 (76). Aged PCs may even modulate myelopoiesis, reportedly in an IL-10-and TLR-dependent manner (158,159). This is relevant, since myeloid cells and progenitors are important producers of PC survival factors (71,73,74,87) and may provide a positive-feedback loop. ...
... Aside from the above, ASCs influence homeostatic processes such as hematopoiesis. 16,17 Although hematopoietic regulatory capacity has been ascribed to bone marrow (BM) ASCs, whether ASCs regulate hematopoietic processes in other organs such as the thymus (THY) remains to be determined. ...
... [9][10][11] In addition, this same secretory ability may influence their potential to regulate BM hematopoiesis. 16,17 As a result, understanding ASC biology is of growing importance as the repertoire of ASC functions seems to depend on the context in which ASCs exist. Along these lines, recent studies have utilized RNA-seq at both bulk 13,17,91,92 and single cell 56,93 levels in an attempt to define different ASC subsets or functional states. ...
Antibody-secreting cells (ASCs) are key contributors to humoral immunity through immunoglobulin production and the potential to be long-lived. ASC persistence has been recognized in the autoimmune thymus (THY); however, only recently has this population been appreciated in healthy THY tissue. We showed that the young female THY was skewed toward higher production of ASCs relative to males. However, these differences disappeared with age. In both sexes, THY ASCs included Ki-67+ plasmablasts which required CD154(CD40L) signals for their propagation. Single cell RNA-sequencing revealed that THY ASCs were enriched for an interferon responsive transcriptional signature relative to those from bone marrow and spleen. Flow cytometry confirmed that THY ASCs had increased levels of Toll-like receptor 7 as well as CD69 and major histocompatibility complex class II. Overall, we identified fundamental aspects of THY ASC biology which may be leveraged for future in depth studies of this population in both health and disease.
... In addition, IL-10 plays a role in maintaining the self-renewal of hematopoietic stem cells during physiological hematopoiesis (Camacho et al., 2020). Bone marrow (BM)-resident regulatory T cells (Tregs) and plasma cells have been reported as IL-10 producers in naive and in BM-transplanted mice (Fujisaki et al., 2011;Meng et al., 2019). Regulatory B cells are characterized by the capacity to produce anti-inflammatory cytokines, such as IL-10, and coordinate the pathogenesis of multiple inflammatory disorders (Mauri, 2021;Ran et al., 2020). ...
... Importantly, B cells were the largest population among the Il10expressing cells, and the B cell expression level of Il10 was the highest among the Il10-expressing populations (Fig. 4 f). Tregs and plasma cells are possible sources of IL-10 in the BM under naive conditions or after BM transplantation (Fujisaki et al., 2011;Meng et al., 2019). However, the number of Tregs was strongly reduced (Fig. S3, c and d) and plasma cells disappeared (Fig. S3, e and f) in the BM after LPS treatment as previously reported in systemic Toxoplasma gondii infections (Glatman Zaretsky et al., 2017). ...
... IL-10 is an anti-inflammatory molecule that maintains tissue homeostasis. Tregs and plasma cells have been reported to be sources of IL-10 in the BM (Fujisaki et al., 2011;Meng et al., 2019). However, it had not been clear which cells supply IL-10 in the BM after infection. ...
Emergency myelopoiesis (EM) is a hematopoietic response against systemic infections that quickly supplies innate immune cells. As lymphopoiesis is strongly suppressed during EM, the role of lymphocytes in that process has not received much attention. Here, we found that myeloid-like B cells (M-B cells), which express myeloid markers, emerge in the bone marrow (BM) after the induction of EM. M-B cells were mainly derived from pre-B cells and preferentially expressed IL-10, which directly stimulates hematopoietic progenitors to enhance their survival and myeloid-biased differentiation. Indeed, lacking IL-10 in B cells, blocking IL-10 in the BM with a neutralizing antibody, and deleting the IL-10 receptor in hematopoietic progenitors significantly suppressed EM, which failed to clear microbes in a cecal ligation and puncture model. Thus, a distinct B cell subset generated during infection plays a pivotal role in boosting EM, which suggests the on-demand reinforcement of EM by adaptive immune cells.
... TACI is an immune regulatory molecule that promotes the differentiation and survival of plasma cells [58]. Since plasma cells are a known source of IL-10 [59], enhanced TACI expression in WT dams may contribute to their enhanced IL-10 expression. Besides, expression of TACI by B1b cells was shown to be induced by TLR signaling and provided a heightened protective response [60]. ...
B cells and in particular IL-10-secreting B cells emerge as important players in immune balance during pregnancy. We have recently revealed that CD19-deficient (CD19−/−), B cell-specific IL-10-deficient (BIL-10−/−) and B cell-deficient µMT pregnant mice are highly susceptible to LPS-induced preterm birth (PTB). We aimed to analyze the ability of IL-10-secreting cells to protect from PTB and the underlying mechanisms. Wild type (WT), CD19−/−, BIL-10−/− and µMT mice were treated with LPS at gd16 and the cellular immune response was investigated 24 h later. LPS-treated BIL-10−/− dams showed a more pronounced PTB phenotype compared to WT, CD19−/− and µMT females, and increased inflammatory and reduced anti-inflammatory mediator concentrations in the peritoneal cavity and serum. CD19−/−, BIL-10−/− and µMT mice displayed altered immune cell population frequencies in the blood and uterus with lower numbers of IL-10-secreting B cells and T cells. BIL-10−/− mothers presented decreased frequencies of uterine CD4+CD25+Foxp3+ Treg cells. Co-stimulatory molecules are critical for feto-maternal tolerance and IL-10 secretion. We found dysregulated PD-1 expression in peripheral blood and ICOS expression in the uterus of CD19−/−, BIL-10−/− and µMT dams. Our data show that B cell-specific IL-10-signaling is essential for a balanced maternal immune response to an inflammatory stimulant that cannot be hampered without IL-10-secreting B cells.
... Under this context, a flow of CD45 + cells from the bone marrow to the systemic circulation, but not to the spleen, occurs. Among them, immature myeloid cells (Ly6C + CD11b + ) appear to exit the bone marrow and have been previously characterized [63,64]. We hypothesized that part of these cells is mobilized toward the spleen due to the enhanced presence of CXCL12 in this organ [38]. ...
In the course of atherogenesis, the spleen plays an important role in the regulation of extramedullary hematopoiesis, and in the control of circulating immune cells, which contributes to plaque progression. Here, we have investigated the role of splenic nucleotide-binding oligomerization domain 1 (NOD1) in the recruitment of circulating immune cells, as well as the involvement of this immune organ in extramedullary hematopoiesis in mice fed on a high-fat high-cholesterol diet (HFD). Under HFD conditions, the absence of NOD1 enhances the mobilization of immune cells, mainly neutrophils, from the bone marrow to the blood. To determine the effect of NOD1-dependent mobilization of immune cells under pro-atherogenic conditions, Apoe−/− and Apoe−/−Nod1−/− mice fed on HFD for 4 weeks were used. Splenic NOD1 from Apoe−/− mice was activated after feeding HFD as inferred by the phosphorylation of the NOD1 downstream targets RIPK2 and TAK1. Moreover, this activation was accompanied by the release of neutrophil extracellular traps (NETs), as determined by the increase in the expression of peptidyl arginine deiminase 4, and the identification of citrullinated histone H3 in this organ. This formation of NETs was significantly reduced in Apoe−/−Nod1−/− mice. Indeed, the presence of Ly6G⁺ cells and the lipidic content in the spleen of mice deficient in Apoe and Nod1 was reduced when compared to the Apoe−/− counterparts, which suggests that the mobilization and activation of circulating immune cells are altered in the absence of NOD1. Furthermore, confirming previous studies, Apoe−/−Nod1−/− mice showed a reduced atherogenic disease, and diminished recruitment of neutrophils in the spleen, compared to Apoe−/− mice. However, splenic artery ligation reduced the atherogenic burden in Apoe−/− mice an effect that, unexpectedly was lost in Apoe−/−Nod1−/− mice. Together, these results suggest that neutrophil accumulation and activity in the spleen are driven in part by NOD1 activation in mice fed on HFD, contributing in this way to regulating atherogenic progression.
... The hallmark of the immune response durability is the formation of long-term memory immune cells including memory B and T lymphocytes and plasma cells. Apart from their known function at the forefront in secreting protective antibodies, plasma cells have recently been appreciated for their role in many biological functions through cytokines production [23][24][25][26][27][28]. Furthermore, although circulating antibodies are mainly produced by long-lived plasma cells, some reports suggest that short-lived plasmablasts could also persist and participate in maintaining antigen-specific circulating antibodies levels [29,30]. ...
Background:
The Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic zoonotic betacoronaviruses and a global public health concern. Better undersetting of the immune responses to MERS-CoV is needed to characterize the correlates of protection and durability of the immunity and to aid in developing preventative and therapeutic interventions. While MERS-CoV-specific circulating antibodies could persist for several years post-recovery, their waning raises concerns about their durability and role in protection. Nonetheless, memory B and T cells could provide long-lasting protective immunity despite the serum antibodies levels.
Methods:
Serological and flow cytometric analysis of MERS-CoV-specific immune responses were performed on samples collected from a cohort of recovered individuals who required intensive care unit (ICU) admission as well as hospital or home isolation several years after infection to characterize the longevity and quality of humoral and cellular immune responses.
Results:
Our data showed that MERS-CoV infection could elicit robust long-lasting virus-specific binding and neutralizing antibodies as well as T and B cell responses up to 6.9 years post-infection regardless of disease severity or need for ICU admission. Apart from the persistent high antibody titers, this response was characterized by B cell subsets with antibody-independent functions as demonstrated by their ability to produce TNF-α, IL-6, and IFN-γ cytokines in response to antigen stimulation. Furthermore, virus-specific activation of memory CD8+ and CD4+ T cell subsets from MERS-recovered patients resulted in secretion of high levels of TNF-α, IL-17 and IFN-γ.
Conclusions:
MERS-CoV infection could elicit robust long-lasting virus-specific humoral and cellular responses.
... Under this context, a flow of CD45 + cells from the bone marrow to systemic circulation, but not to the spleen, occurs. Among them, immature myeloid cells (Ly6C + CD11b + ) appear to exit the bone marrow and have been previously characterized (57,58). We hypothesized that part of these cells are mobilized towards the spleen due to the enhanced presence of CXCL12 in this organ (34). ...
In the course of atherogenesis, the spleen plays an important role in the regulation of extramedullary hematopoiesis and in the control of circulating immune cells, which contributes to plaque progression. Here, we have investigated the role of splenic nucleotide-binding oligomerization domain 1 (NOD1) in the recruitment of circulating immune cells as well as the involvement of this immune organ in extramedullary hematopoiesis in mice fed a high-fat high-cholesterol diet (HFD). Under HFD conditions, the absence of NOD1 enhances the mobilization of immune cells, mainly neutrophils, from the bone marrow to the blood. To determine the effect of NOD1-dependent mobilization of immune cells under pro-atherogenic conditions, Apoe -/- and Apoe -/- Nod1 -/- mice fed HFD for 4 weeks were used. Splenic NOD1 from Apoe -/- mice was activated after feeding HFD as inferred by the phosphorylation of the NOD1 downstream targets RIPK2 and TAK1. Moreover, this activation was accompanied by the release of neutrophil extracellular traps (NETs), as determined by the increase in the expression of peptidyl arginine deiminase 4, and the identification of citrullinated histone H3 in this organ. This formation of NETs was significantly reduced in Apoe -/- Nod1 -/- mice. Indeed, the presence of Ly6G + cells and the lipidic content in the spleen of mice deficient in Apoe and Nod1 was reduced when compared to the Apoe -/- counterparts, which suggests that the mobilization and activation of circulating immune cells is altered in the absence of NOD1. Furthermore, confirming previous studies, Apoe -/- Nod1 -/- mice showed a reduced atherogenic disease and a diminished recruitment of neutrophils in the spleen, compared to Apoe -/- mice. However, splenic artery-ligation reduced the atherogenic burden in Apoe -/- mice an effect that, unexpectedly was lost in Apoe -/- Nod1 -/- mice. Together, these results suggest that neutrophil accumulation and activity in the spleen is driven in part by NOD1 activation in mice fed HFD, contributing in this way to regulate atherogenic progression.
