Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens (human) Mus musculus (mouse)
SUBMITTER:
PROVIDER: S-BSST1437 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:In humans, blood Classical CD14+ monocytes contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with 'immunoparalysis', a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is critical to prevent these harmful outcomes. We reveal platelets' vital role in the pro-inflammatory cytokine responses of human monocytes. Naturally low platelet counts in patients with immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.
| S-EPMC11319489 | biostudies-literature
Project description:Classical CD14+ monocytes in human blood contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with 'immunoparalysis', a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is therefore paramount. We reveal platelets' vital role in human monocytes' pro-inflammatory cytokine responses. Naturally, low platelet counts in immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.
| S-SCDT-10_1038-S44321-024-00093-3 | biostudies-other
Project description:CD14+ monocytes, the predominant population in human blood, are primarily engaged in host defense and pro-inflammatory cytokine responses. Aberrant monocyte activity causes life-threatening cytokine storms, while dysfunctional monocytes lead to 'immunoparalysis.' Understanding the mechanisms controlling monocyte functions is therefore paramount. Here, we reveal platelets' vital role in human monocytes' pro-inflammatory responses. Natural low platelet counts in patients with immune thrombocytopenia (ITP) , platelet depletion in healthy human monocytes, or in vivo platelet depletion in mice, result in monocyte immunoparalysis, characterized by reduced pro-inflammatory gene expression and weakened cytokine responses to immune challenge. Remarkably, supplementation with fresh platelets reverses monocyte immunoparalysis. In mice, thrombocytopenia results in down-regulation of myeloid innate immune genes, and compromised host defense transcriptional programs in monocytes despite normal responses to LPS. Platelets control monocyte cytokines independently of traditional cross-talk pathways, acting as reservoirs of transcription factors like NF?B and MAPK p38. We pinpointed a vesicle-derived NF?B2 transfer to human monocytes by mass spectrometry-based proteomics. Functionally, platelets proportionally restored impaired cytokine secretion in human monocytes lacking MAPK p38a and NF?B p65 and NF?B2. We unveil the intercellular transfer of inflammatory regulators, positioning platelets as central checkpoints in monocyte-mediated inflammation.
2024-08-14 | PXD052113 | Pride
Project description:NFAT activating protein with ITAM motif 1 (NFAM1) is an ITAM bearing-transmembrane receptor that has been reported to play a role in B cell signaling and development. We performed expression analysis of NFAM1 using publicly available gene expression data sets and found that NFAM1 expression is significantly induced in intestinal biopsies from Crohn's disease (CD) and ulcerative colitis (UC) patients. At the cellular level, we further observed high expression of NFAM1 in monocytes and neutrophils, and low expression in B and T cells. To explore the role of NFAM1 in multiple immune cells and its potential role in IBD, we generated NFAM1-/- mice. In contrast with previous reports using NFAM1-transgenic mice, NFAM1-/- mice have no obvious defects in immune cell development, or B cell responses. Interestingly, NFAM1-/- monocytes produce reduced levels of TNF-α in response to activation by multiple IBD-relevant stimuli, including CD40L, TLR ligands and MDP. Additional cytokines and chemokines such as IL-6, IL-12, CCL3 and CCL4 are also reduced in CD40L stimulated NFAM1-/- monocytes. Collectively, these findings indicate that NFAM1 promotes monocyte activation, thereby amplifying the response to diverse stimuli. Similarly, we observed that deletion of NFAM1 in human monocytes reduces expression of CD40L-induced CCL4. Lastly, to assess the role of NFAM1 in IBD, we compared development of anti-CD40 induced colitis in NFAM1+/+ and NFAM1-/- mice. We found that although NFAM1 deletion had no impact on development of gut pathology, we did observe a decrease in serum TNF-α, confirming that NFAM1 promotes pro-inflammatory cytokine production in vivo. Taken together, we conclude that NFAM1 functions to amplify cytokine production and should be further evaluated as a therapeutic target for treatment of autoimmune disease.
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Project description:Tim-3 and PD-1 are powerful immunoinhibitory molecules involved in immune tolerance, autoimmune responses, and antitumor or antiviral immune evasion. A current model for Tim-3 regulation during immune responses suggests a divergent function, such that Tim-3 acts synergistically with TLR signaling pathways in innate immune cells to promote inflammation, yet the same molecule terminates Th1 immunity in adaptive immune cells. To better understand how Tim-3 might be functioning in innate immune responses, we examined the kinetics of Tim-3 expression in human CD14+ M/M(Ф) in relation to expression of IL-12, a key cytokine in the transition of innate to adaptive immunity. Here, we show that Tim-3 is constitutively expressed on unstimulated peripheral blood CD14+ monocytes but decreases rapidly upon TLR stimulation. Conversely, IL-12 expression is low in these cells but increases rapidly in CD14+ M/M(Ф) in correlation with the decrease in Tim-3. Blocking Tim-3 signaling or silencing Tim-3 expression led to a significant increase in TLR-mediated IL-12 production, as well as a decrease in activation-induced up-regulation of the immunoinhibitor, PD-1; TNF-α production was not altered significantly, but IL-10 production was increased. These results suggest that Tim-3 has a role as a regulator of pro- and anti-inflammatory innate immune responses.
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Project description:The proper functioning of the immune system depends on an appropriate balance between pro-inflammation and anti-inflammation. When the balance is disrupted and the system is excessively biased towards inflammation, immune responses cannot return within the normal range, which favors the onset of diseases of autoimmune or inflammatory nature. In this scenario, it is fundamental to find new compounds that can help restore this balance and contribute to the normal functioning of the immune system in humans. Here, we show the properties of a fungal compound with a strong safety profile in humans, AM3, as an immunomodulatory molecule to decrease excessive cytokine production in human cells. Our results present that AM3 treatment of human peripheral blood mononuclear cells and monocytes decreased their pro-inflammatory cytokine secretion following the challenge with bacterial lipopolysaccharide. Additionally, AM3 skewed the differentiation profile of human monocytes to macrophages towards a non-inflammatory phenotype without inducing tolerance, meaning these cells kept their capacity to respond to different stimuli. These effects were similar in young and elderly individuals. Thus, the fungal compound, AM3 may help reduce excessive immune activation in inflammatory conditions and keep the immune responses within a normal homeostatic range, regardless of the age of the individual.
| S-EPMC10591448 | biostudies-literature
Project description:NFAM1 is an ITAM bearing-transmembrane receptor. Based on overexpression studies, NFAM1 is reported to play a role in B cell signaling and development. We performed expression analysis of NFAM1 in publicly available gene expression data sets and discovered that NFAM1 expression is significantly induced in intestinal biopsies from Crohn’s disease (CD) and ulcerative colitis (UC) patients. At the cellular level, we observed high expression of NFAM1 in monocytes and neutrophils, in addition to expression in B and T cells. To explore the role of NFAM1 in multiple immune cells and its potential role in IBD, we generated NFAM1-/- mice. Contrary to previous reports using NFAM1-transgenic mice, NFAM1-/- mice have no obvious defects in immune cell development, or in T cell-dependent or independent B cell responses. Interestingly, NFAM1-/- monocytes produce reduced levels of TNF-α in response to activation by multiple IBD-relevant stimuli, including CD40L, TLR ligands and MDP. Collectively, these findings indicate that NFAM1 promotes pro-inflammatory monocyte development, thereby amplifying the response to diverse stimuli. These findings are not mouse-specific, as we found that deletion of NFAM1 in human monocytes also reduced expression of CD40L-induced CCL4.
2022-01-03 | GSE188390 | GEO
Project description:Background:Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation. Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-?, interleukin (IL)-1?, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4. Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-?, IL-1? and IL-8 in term neonatal and adult monocytes (p < 0.01 and p < 0.05). Intracellular protein expression of TNF-?, IL-1? and IL-8 in Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1? in adult monocytes (Uu8: p < 0.05). Remarkably, ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1?/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p < 0.01, vs. LPS). In contrast to LPS, both isolates induced TLR2 mRNA in neonatal and adult cells (p < 0.001 and p < 0.05) and suppressed TLR4 mRNA in adult monocytes (p < 0.05). Upon co-stimulation, Uu8 and Up3 inhibited LPS-induced intracellular IL-1? (p < 0.001 and p < 0.05) and IL-8 in adult monocytes (p < 0.01), while LPS-induced neonatal cytokines were maintained or aggravated (p < 0.05). Conclusion: Our data demonstrate a considerable pro-inflammatory capacity of Ureaplasma isolates in human monocytes. Stimulating pro-inflammatory cytokine responses while hardly inducing immunomodulatory and anti-inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of TLR2 and TLR4 expression may shape host susceptibility to inflammation.
| S-EPMC5712342 | biostudies-literature
Project description:BackgroundHepatitis C virus (HCV) dysregulates innate and adaptive immune responses while monocytes (M) play a crucial role in linking innate and adaptive immunity to control viral infection. A transcription factor T-bet is upregulated to dampen M functions via the c-Jun N-terminal kinase (JNK) pathway, followed by enhanced Tim-3 expression in chronic HCV infection. However, the molecular mechanisms that control the expression in M are yet unknown. miR-155 has been implicated as a key regulator controlling diverse biological processes through posttranscriptional repression, but the influences of miR-155 on these regulators and effectors still need to be studied.MethodsForty HCV-infected patients and 40 healthy subjects (HS) were recruited, THP-1 cells (human acute monocyte leukemia cell line) were cultured with HCV-infected Huh 7.5 cells. The expression levels of miR-155 and JNK1/JNK2/JNK3 were measured by real-time RT-PCR. IL-10/IL-12 was detected by flow cytometry. THP-1 cells were transfected with mimics-155 and negative control, SOCS1, p-STAT1, p65, p-smad, p-p38, and p-JNK were measured by Western blot. TNF-α levels were measured by ELISA. Student's t-test was used in statistics.ResultsThe study showed that miR-155 was upregulated in CD14+ M in HCV-infected patients compared to healthy subjects (P<0.05). Moreover, the upregulation of miR-155 in CD14+ M from HCV-infected patients induced TNF-α production and JNK gene expression, which, in turn, led to T-bet upregulation. Also, miR-155 upregulation in CD14+ M of HCV-infected patients increased the IL-12 and decreased the IL-10 production.ConclusionsThe obtained results indicated that miR-155 upregulation in M during HCV infection enhances the activation of TNF-α and JNK pathways, promotes the expression of transcription factor T-bet, and triggers pro- and anti-inflammatory mediators. Together, these data reveal new information regarding the mechanisms of chronic HCV infection.
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Project description:The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery. By limiting activity to targeted loci, Syn-TEFs convert constituent modules from broad-spectrum inhibitors of transcription into gene-specific stimulators. Here we present Syn-TEF1, a molecule that actively enables transcription across repressive GAA repeats that silence frataxin expression in Friedreich's ataxia, a terminal neurodegenerative disease with no effective therapy. The modular design of Syn-TEF1 defines a general framework for developing a class of molecules that license transcription elongation at targeted genomic loci.
| S-EPMC6037176 | biostudies-literature