Maternal circadian rhythm disruption affects neonatal inflammation via metabolic reprograming of myeloid cells.

Disruption of circadian rhythm during pregnancy produces adverse health outcomes in offspring; however, the role of maternal circadian rhythms in the immune system of infants and their susceptibility to inflammation remains poorly understood. Here we show that disruption of circadian rhythms in pregnant mice profoundly aggravates the severity of neonatal inflammatory disorders in both male and female offspring, such as necrotizing enterocolitis and sepsis. The diminished maternal production of docosahexaenoic acid (DHA) and the impaired immunosuppressive function of neonatal myeloid-derived suppressor cells (MDSCs) contribute to this phenomenon. Mechanistically, DHA enhances the immunosuppressive function of MDSCs via PPARγ-mediated mitochondrial oxidative phosphorylation. Transfer of MDSCs or perinatal supplementation of DHA relieves neonatal inflammation induced by maternal rhythm disruption. These observations collectively demonstrate a previously unrecognized role of maternal circadian rhythms in the control of neonatal inflammation via metabolic reprograming of myeloid cells.

Decreased melanoma CSF-1 secretion by Cannabigerol treatment reprograms regulatory myeloid cells and reduces tumor progression.

During solid tumor progression, the tumor microenvironment (TME) evolves into a highly immunosuppressive milieu. Key players in the immunosuppressive environment are regulatory myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which are recruited and activated via tumor-secreted cytokines such as colony-stimulating factor 1 (CSF-1). Therefore, the depletion of tumor-secreted cytokines is a leading anticancer strategy. Here, we found that CSF-1 secretion by melanoma cells is decreased following treatment with Cannabis extracts. Cannabigerol (CBG) was identified as the bioactive cannabinoid responsible for the effects. Conditioned media from cells treated with pure CBG or the high-CBG extract reduced the expansion and macrophage transition of the monocytic-MDSC subpopulation. Treated MO-MDSCs also expressed lower levels of iNOS, leading to restored CD8+ T-cell activation. Tumor-bearing mice treated with CBG presented reduced tumor progression, lower TAM frequencies and reduced TAM/M1 ratio. A combination of CBG and αPD-L1 was more effective in reducing tumor progression, enhancing survival and increasing the infiltration of activated cytotoxic T-cells than each treatment separately. We show a novel mechanism for CBG in modulating the TME and enhancing immune checkpoint blockade therapy, underlining its promising therapeutic potential for the treatment of a variety of tumors with elevated CSF-1 expression.

Delicaflavone reactivates anti-tumor immune responses by abrogating monocytic myeloid cell-mediated immunosuppression.

BACKGROUND: Myeloid cell-mediated immunosuppression is a major obstacle to checkpoint blockade immunotherapy. We previously reported that total biflavonoids extract from Selaginella doederleinii (TBESD) and a flavone monomer isolated from TBESD, named Delicaflavone, have favorable anti-tumor activity. However, whether TBESD and Delicaflavone could affect the tumor microenvironment (TME) remains unclear. PURPOSE: In this study, we focused on the TME to determine whether TBESD and Delicaflavone could restore anti-tumor immune response. METHODS: 4T1 tumor-bearing immunocompetent BALB/c mice and T cell-deficient nude mice were used to examine the effect of TBESD on T cell-mediated immunity in vivo. Multi-parameter flow cytometry was conducted to evaluate the impacts of TBESD on TME. Primary cells, including murine CD8+ T cells, tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) were prepared to investigate the modulatory activities of TBESD on immune cells. It was further determined whether Delicaflavone or Amentoflavone, two typical functional biflavones from TBESD, mediated those effects of TBESD. Finally, the impacts of TBESD and Delicaflavone on Jak1/STAT6 signaling pathway were explored via western blot. RESULTS: We found that TBESD significantly reduced 4T1 tumor growth in immunocompetent BALB/c mice, but not in nude mice. This effect was associated with the regulation of TME, shown as an increase in functional T cells and M1 phenotype TAMs (M1-TAMs), and a decrease in M2 phenotype TAMs (M2-TAMs), monocytic-MDSCs (M-MDSCs) and regulatory T cells (Tregs) in TBESD-treated BALB/c mouse 4T1 tumors. It was found ex vivo that TBESD restrained the viability and immunosuppressive properties of M2-TAMs and M-MDSCs, especially for the loss of arginase-1 expression. Additionally, TBESD re-educated M2-TAMs to an M1 like phenotype. Further investigations determined that Delicaflavone predominantly mediated the immuno-modulatory activities of TBESD both ex vivo and in vivo. Finally, Delicaflavone and TBESD blocked Jak1/STAT6 signaling pathway in M2-TAMs and MDSCs. CONCLUSION: The present study suggests Delicaflavone as a potent natural inhibitor of M2-TAMs and MDSCs, which fills the gap in knowledge on the immuno-modulatory effects of TBESD and Delicaflavone, and could have translational implications to improve the efficacy of cancer immunotherapy.

The Yin-Yang of myeloid cells in the leukemic microenvironment: Immunological role and clinical implications.

The leukemic microenvironment has a high diversity of immune cells that are phenotypically and functionally distinct. However, our understanding of the biology, immunology, and clinical implications underlying these cells remains poorly investigated. Among the resident immune cells that can infiltrate the leukemic microenvironment are myeloid cells, which correspond to a heterogeneous cell group of the innate immune system. They encompass populations of neutrophils, macrophages, and myeloid-derived suppressor cells (MDSCs). These cells can be abundant in different tissues and, in the leukemic microenvironment, are associated with the clinical outcome of the patient, acting dichotomously to contribute to leukemic progression or stimulate antitumor immune responses. In this review, we detail the current evidence and the many mechanisms that indicate that the activation of different myeloid cell populations may contribute to immunosuppression, survival, or metastatic dissemination, as well as in immunosurveillance and stimulation of specific cytotoxic responses. Furthermore, we broadly discuss the interactions of tumor-associated neutrophils and macrophages (TANs and TAMs, respectively) and MDSCs in the leukemic microenvironment. Finally, we provide new perspectives on the potential of myeloid cell subpopulations as predictive biomarkers of therapeutical response, as well as potential targets in the chemoimmunotherapy of leukemias due to their dual Yin-Yang roles in leukemia.

Cellular cross-talk in heart repair.

The cytokine meteorin-like (METRNL) improves cardiac function after heart attack in mice.

Vitexin restores lung homeostasis by targeting vicious loop between inflammatory aggravation and autophagy mediated via multiple redox cascade and myeloid cells alteration in experimental allergic asthma.

BACKGROUND: Allergic asthma is one of the leading respiratory diseases with complex pathology. Attributes of vitexin, a trihydroxyflavone, has been studied to alleviate Th2 cytokines response in allergic asthma. However, its efficacy and underlying mechanism in mitigating allergic asthma particularly mediated by oxi-inflammatory stress, autophagy and apoptosis, yet to be delineated. PURPOSE: Present study aimed to decipher efficacy and governing molecular mechanism of vitexin in mitigating allergic asthma particularly mediated by vicious loop of oxi-inflammatory stress, autophagy and apoptosis. METHODS: To ascertain this, OVA-LPS induced mice model was used and protective attributes of vitexin for different mediators, pathological facets and sensing pathways of allergic asthma were evaluated. RESULTS: Vitexin treatment remarkably inhibited OVA-LPS induced inflammatory cell infiltration, mast cell activation, alveolar collapse, congestion, fibrosis in lung architecture. These results were accompanied by suppression of immune cells hyperactivation, mucus secretion, goblet cell proliferation, persistent inflammation which were affirmed by alleviation in levels of IgE, Th1/Th2/Th17, IL-4/IFN-γ, chemokines, endopeptidases (MMP-1, MMP-13), oxidative effectors with concomitant increase in IL-15, IL-10, MMP-9 and MMP-3. Additionally, noticeable decline in p-connexin 43, p-c-Fos, TGF-ß, Smad2/3/4, Caspase9/3, LC3A/B expression and upregulation in beclin-1, p62 co-localization and Bcl2/Bax indicate reversal of lung vascular permeability, mast cell degranulation, fibrosis, apoptosis, autophagosome impairment. Subsequent allergic inflammatory cascades analysis revealed p-NF-κB, p-PI3K, p-Akt, p-p38, p-Stat3, GATA3 upregulation and p-PTEN downregulation in sensitized mice, which were decisively counteracted by vitexin. In silico studies signified target specificity of vitexin with these proteins. Suppression in myeloid cells activation and enhancements of Tregs demonstrated immunomodulatory potential of vitexin in allergic airways. CONCLUSION: Collectively, to our knowledge, this is the first report that confers vitexin meditated multi-faceted protective attribute in mitigation of allergic asthma that could be linked to its suppressive effects on vicious cycle of pathological process particularly regulated via oxi-inflammation, autophagy and apoptosis. Thus, signify vitexin as safe therapeutic strategy.

Protective effect of green tea and epigallocatechin-3-gallate in a LPS-induced systemic inflammation model.

Inflammation causes severe dysregulation of organ functions, via the development of oxidative stress and inflammation damage. Polyphenol compounds found in green tea (GTE), including the most important component epigallocatechin-3-gallate (EGCG), have a great therapeutic potential. Here, protective properties of GTE and EGCG against lipopolysaccharide (LPS)-induced inflammation are explored. To this end, the effects of GTE and EGCG were studied on LPS challenged macrophages. Mice received GTE (250 mg/kg/d/p.o) or EGCG (25 mg/kg/d/i.p.) for 7 d, before the inflammation shock was provoked with a single intraperitoneal injection of LPS. The frequencies of lymphocytes CD4+, CD8+, NK1-1+ and CD4+CD25highFOXP3+ (Treg), macrophages CD11b+F480+, monocytes CD11b+Ly6Clow/high, neutrophils CD11b+Ly6G+, MDSCs CD11b+Gr-1high, M2/N2-like phenotype CD206+ and M1-like phenotype CD86+ in spleen, bone marrow and peripheral blood were determined. In vitro studies revealed that GTE and EGCG significantly attenuated LPS-induced CD80 expression and increased the CD163 expression, showing a potential to reduce the macrophage inflammatory phenotype. In vivo, GTE and EGCG inhibited the inflammation, mainly by reducing M1-macrophages and increasing Treg cells in the bone marrow. In addition, GTE and EGCG increase M2-macrophages, N2-neutrophils and Tregs in the spleen and blood and block the migration of monocytes from the bone marrow to the peripheral blood. These findings indicate that EGCG and GTE prevent LPS-induced inflammatory damage contributing to restoring the immune system homeostasis.

Myeloid-Derived Suppressor Cells in Trypanosoma cruzi Infection.

Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous myeloid cells that expand in pathologic conditions as cancer, trauma, and infection. Although characterization of MDSCs is continuously revisited, the best feature is their suppressor activity. There are many markers for MDSC identification, it is distinctive that they express inducible nitric oxide synthase (iNOS) and arginase 1, which can mediate immune suppression. MDSCs can have a medullary origin as a result of emergency myelopoiesis, but also can have an extramedullary origin. Early studies on Trypanosoma cruzi infection showed severe immunosuppression, and several mechanisms involving parasite antigens and host cell mediators were described as inhibition of IL-2 and IL-2R. Another mechanism of immunosuppression involving tumor necrosis factor/interferon γ-dependent nitric oxide production by inducible nitric oxide synthase was also described. Moreover, other studies showed that nitric oxide was produced by CD11b+ Gr-1+ MDSCs in the spleen, and later iNOS and arginase 1 expressed in CD11b+Ly6C+Ly6Glo monocytic MDSC were found in spleen and heart of T. cruzi infected mice that suppressed T cell proliferation. Uncontrolled expansion of monocytic MDSCs leads to L-arginine depletion which hinders nitric oxide production leading to death. Supplement of L-arginine partially reverts L-arginine depletion and survival, suggesting that L-arginine could be administered along with anti-parasitical drugs. On the other hand, pharmacological inhibition of MDSCs leads to death in mice, suggesting that some expansion of MDSCs is needed for an efficient immune response. The role of signaling molecules mediating immune suppression as reactive oxygen species, reactive nitrogen species, as well as prostaglandin E2, characteristics of MDSCs, in T. cruzi infection is not fully understood. We review and discuss the role of these reactive species mediators produced by MDSCs. Finally, we discuss the latest results that link the SLAMF1 immune receptor with reactive oxygen species. Interaction of the parasite with the SLAMF1 modulates parasite virulence through myeloid cell infectivity and reactive oxygen species production. We discuss the possible strategies for targeting MDSCs and SLAMF1 receptor in acute Trypanosoma cruzi infection in mice, to evaluate a possible translational application in human acute infections.

Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer.

PURPOSE: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. EXPERIMENTAL DESIGN: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). RESULTS: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. CONCLUSIONS: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).

Neuroblastoma Formation Requires Unconventional CD4 T Cells and Arginase-1-Dependent Myeloid Cells.

Immune cells regulate tumor growth by mirroring their function as tissue repair organizers in normal tissues. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunologic manipulation with noninvasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Spatial transcriptomic analysis showed that CD4+ and myeloid populations colocalized within the tumor parenchyma, while CD8+ T cells and B cells were peripherally dispersed. Depletion of CD4+ T cells or CCR2+ macrophages, but not B cells, CD8+ T cells, or natural killer (NK) cells, prevented tumor formation. Tumor CD4+ T cells displayed unconventional phenotypes and were clonotypically diverse and antigen independent. Within the myeloid fraction, tumor growth required myeloid cells expressing arginase-1. Overall, these results demonstrate how arginine-metabolizing myeloid cells conspire with pathogenic CD4+ T cells to create permissive conditions for tumor formation, suggesting that these protumorigenic pathways could be disabled by targeting myeloid arginine metabolism. SIGNIFICANCE: A new model of human neuroblastoma provides ways to track tumor formation and expansion in living animals, allowing identification of CD4+ T-cell and macrophage functions required for oncogenesis.

A BMPR2/YY1 Signaling Axis Is Required for Human Cytomegalovirus Latency in Undifferentiated Myeloid Cells.

Human cytomegalovirus (HCMV) presents a major health burden in the immunocompromised and in stem cell transplant medicine. A lack of understanding about the mechanisms of HCMV latency in undifferentiated CD34+ stem cells, and how latency is broken for the virus to enter the lytic phase of its infective cycle, has hampered the development of essential therapeutics. Using a human induced pluripotent stem cell (iPSC) model of HCMV latency and patient-derived myeloid cell progenitors, we demonstrate that bone morphogenetic protein receptor type 2 (BMPR2) is necessary for HCMV latency. In addition, we define a crucial role for the transcription factor Yin Yang 1 (YY1) in HCMV latency; high levels of YY1 are maintained in latently infected cells as a result of BMPR2 signaling through the SMAD4/SMAD6 axis. Activation of SMAD4/6, through BMPR2, inhibits TGFbeta receptor signaling, which leads to the degradation of YY1 via induction of a cellular microRNA (miRNA), hsa-miR-29a. Pharmacological targeting of BMPR2 in progenitor cells results in the degradation of YY1 and an inability to maintain latency and renders cells susceptible to T cell killing. These data argue that BMPR2 plays a role in HCMV latency and is a new potential therapeutic target for maintaining or disrupting HCMV latency in myeloid progenitors. IMPORTANCE Understanding the mechanisms which regulate HCMV latency could allow therapeutic targeting of the latent virus reservoir from where virus reactivation can cause severe disease. We show that the BMPR2/TGFbeta receptor/YY1 signaling axis is crucial to maintain HCMV latency in undifferentiated cells and that pharmacological reduction of BMPR2 in latently infected cells leads to reactivation of the viral lytic transcription program, which renders the infected cell open to immune detection and clearance in infected individuals. Therefore, this work identifies key host-virus interactions which regulate HCMV latent infection. It also demonstrates a potential new therapeutic approach to reduce HCMV reactivation-mediated disease by the treatment of donor stem cells/organs prior to transplantation, which could have a major impact in the transplant disease setting.

The single-cell epigenomic and transcriptional landscape of immunity to influenza vaccination.

Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.

The Immunomodulatory Effects of Honey and Associated Flavonoids in Cancer.

Honey has exerted a high impact in the field of alternative medicine over many centuries. In addition to its wound healing, anti-microbial and antioxidant properties, several lines of evidence have highlighted the efficiency of honey and associated bioactive constituents as anti-tumor agents against a range of cancer types. Mechanistically, honey was shown to inhibit cancer cell growth through its pro-apoptotic, anti-proliferative and anti-metastatic effects. However, the potential of honey to regulate anti-tumor immune responses is relatively unexplored. A small number of in vitro and in vivo studies have demonstrated the ability of honey to modulate the immune system by inducing immunostimulatory as well as anti-inflammatory effects. In the present review, we summarize the findings from different studies that aimed to investigate the immunomodulatory properties of honey and its flavonoid components in relation to cancer. While these studies provide promising data, additional research is needed to further elucidate the immunomodulatory properties of honey, and to enable its utilization as an adjuvant therapy in cancer.

Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy.

Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.

Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation.

Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.

Nutrient supplements from selected botanicals mediated immune modulation of the tumor microenvironment and antitumor mechanism.

Specific extracts of selected vegetables (SV) have been shown to benefit the survival of stage IIIb/IV non-small cell lung cancer patients in phase I/II studies and is currently in a phase III trial. However, the underlying mechanism of SV-mediated antitumor immune responses has not been elucidated. Our results indicate that SV modulated the NK and adoptive T cell immune responses in antitumor efficacy. Furthermore, antitumor effects of SV were also mediated by innate myeloid cell function, which requires both TLR and ß-glucan signaling in a MyD88/TRIF and Dectin-1-dependent manner, respectively. Additionally, SV treatment reduced granulocytic myeloid-derived suppressor cell (MDSC) infiltration into the tumor and limited monocytic MDSC toward the M2-like functional phenotype. Importantly, SV treatment enhanced antigen-specific immune responses by augmenting the activation of antigen-specific TH1/TH17 cells in secondary lymphoid organs and proliferative response, as well as by reducing the Treg population in the tumor microenvironment, which was driven by SV-primed activated M-MDSC. Our results support the idea that SV can subvert immune-tolerance state in the tumor microenvironment and inhibit tumor growth. The present study suggests that features, such as easy accessibility, favorable clinical efficacy, no detectable side effects and satisfactory safety make SV a feasible, appealing and convincing adjuvant therapy for the treatment of cancer patients and prevent tumor recurrence and/or metastases.

Cell type-selective secretome profiling in vivo.

Secreted polypeptides are a fundamental axis of intercellular and endocrine communication. However, a global understanding of the composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte and myeloid cell secretomes by direct purification of biotinylated secreted proteins from blood plasma. Our secretome dataset validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by the increased unconventional secretion of the cytosolic enzyme betaine-homocysteine S-methyltransferase (BHMT). This secretome profiling strategy enables dynamic and cell type-specific dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.

Antiproliferative Effects of St. John's Wort, Its Derivatives, and Other Hypericum Species in Hematologic Malignancies.

Hypericum is a widely present plant, and extracts of its leaves, flowers, and aerial elements have been employed for many years as therapeutic cures for depression, skin wounds, and respiratory and inflammatory disorders. Hypericum also displays an ample variety of other biological actions, such as hypotensive, analgesic, anti-infective, anti-oxidant, and spasmolytic abilities. However, recent investigations highlighted that this species could be advantageous for the cure of other pathological situations, such as trigeminal neuralgia, as well as in the treatment of cancer. This review focuses on the in vitro and in vivo antitumor effects of St. John's Wort (Hypericum perforatum), its derivatives, and other Hypericum species in hematologic malignancies. Hypericum induces apoptosis in both myeloid and lymphoid cells. Other Hypericum targets include matrix metalloproteinase-2, vascular endothelial growth factor, and matrix metalloproteinase-9, which are mediators of cell migration and angiogenesis. Hypericum also downregulates the expression of proteins that are involved in the resistance of leukemia cells to chemotherapeutic agents. Finally, Hypericum and its derivatives appear to have photodynamic effects and are candidates for applications in tumor photodynamic therapy. Although the in vitro studies appear promising, controlled in vivo studies are necessary before we can hypothesize the introduction of Hypericum and its derivatives into clinical practice for the treatment of hematologic malignancies.

Electrostimulation of the carotid sinus nerve in mice attenuates inflammation via glucocorticoid receptor on myeloid immune cells.

BACKGROUND: The carotid bodies and baroreceptors are sensors capable of detecting various physiological parameters that signal to the brain via the afferent carotid sinus nerve for physiological adjustment by efferent pathways. Because receptors for inflammatory mediators are expressed by these sensors, we and others have hypothesised they could detect changes in pro-inflammatory cytokine blood levels and eventually trigger an anti-inflammatory reflex. METHODS: To test this hypothesis, we surgically isolated the carotid sinus nerve and implanted an electrode, which could deliver an electrical stimulation package prior and following a lipopolysaccharide injection. Subsequently, 90 min later, blood was extracted, and cytokine levels were analysed. RESULTS: Here, we found that carotid sinus nerve electrical stimulation inhibited lipopolysaccharide-induced tumour necrosis factor production in both anaesthetised and non-anaesthetised conscious mice. The anti-inflammatory effect of carotid sinus nerve electrical stimulation was so potent that it protected conscious mice from endotoxaemic shock-induced death. In contrast to the mechanisms underlying the well-described vagal anti-inflammatory reflex, this phenomenon does not depend on signalling through the autonomic nervous system. Rather, the inhibition of lipopolysaccharide-induced tumour necrosis factor production by carotid sinus nerve electrical stimulation is abolished by surgical removal of the adrenal glands, by treatment with the glucocorticoid receptor antagonist mifepristone or by genetic inactivation of the glucocorticoid gene in myeloid cells. Further, carotid sinus nerve electrical stimulation increases the spontaneous discharge activity of the hypothalamic paraventricular nucleus leading to enhanced production of corticosterone. CONCLUSION: Carotid sinus nerve electrostimulation attenuates inflammation and protects against lipopolysaccharide-induced endotoxaemic shock via increased corticosterone acting on the glucocorticoid receptor of myeloid immune cells. These results provide a rationale for the use of carotid sinus nerve electrostimulation as a therapeutic approach for immune-mediated inflammatory diseases.

Hand in hand: intrinsic and extrinsic drivers of aging and clonal hematopoiesis.

Over the past 25 years, the importance of hematopoietic stem cell (HSC) aging in overall hematopoietic and immune system health span has been appreciated. Much work has been done in model organisms to understand the intrinsic dysregulation that occurs in HSCs during aging, with the goal of identifying modifiable mechanisms that represent the proverbial "fountain of youth." Much more recently, the discovery of somatic mutations that are found to provide a selective advantage to HSCs and accumulate in the hematopoietic system during aging, termed clonal hematopoiesis (CH), inspires revisiting many of these previously defined drivers of HSC aging in the context of these somatic mutations. To truly understand these processes and develop a holistic picture of HSC aging, ongoing and future studies must include investigation of the critical changes that occur in the HSC niche or bone marrow microenvironment with aging, as increasing evidence supports that these HSC-extrinsic alterations provide necessary inflammation, signaling pathway activation or repression, and other selective pressures to favor HSC aging-associated phenotypes and CH. Here, we provide our perspectives based on the past 8 years of our own laboratory's investigations into these mechanisms and chart a path for integrative studies that, in our opinion, will provide an ideal opportunity to discover HSC and hematopoietic health span-extending interventions. This path includes examining when and how aging-associated HSC-intrinsic and HSC-extrinsic changes accumulate over time in different individuals and developing new models to track and test relevant HSC-extrinsic changes, complementary to innovative HSC lineage tracing systems that have recently been developed.