G-CSF Research Articles

G-CSFR-induced leukocyte transendothelial migration during the inflammatory response is regulated by the ICAM1-PKCa axis: based on multiomics integration analysis

As an indispensable inflammatory mediator during sepsis, granulocyte colony-stimulating factor (G-CSF) facilitates neutrophil production by activating G-CSFR. However, little is known about the role of intracellular downstream signalling pathways in the induction of inflammation. To explore the functions of molecules in regulating G-CSFR signalling, RNA sequencing and integrated proteomic and phosphoproteomic analyses were conducted to predict the differentially expressed molecules in modulating the inflammatory response after G-CSFR expression was either up- or downregulated, in addition to the confirmation of their biological function by diverse experimental methods. In the integrated bioinformatic analysis, 3190 differentially expressed genes (DEGs) and 1559 differentially expressed proteins (DEPs) were identified in multiple-group comparisons (p < 0.05, FC > ± 1.5) using enrichment analyses, as well as those classic pathways such as the TNF, NFkappaB, IL-17, and TLR signalling pathways. Among them, 201 proteins, especillay intercellular cell adhesion molecule-1 (ICAM1) and PKCa, were identified as potential molecules involved in inflammation according to the protein–protein interaction (PPI) analysis, and the leukocyte transendothelial migration (TEM) pathway was attributed to the intervention of G-CSFR. Compared with the control and TNF-a treatment, the G-CSFR (G-CSFROE)-overexpressing led to an obvious increase in the number of leukocytes with the TEM phenotype. Mechanically, the expression of ICAM1 and PKCa was significantly up- and downregulated by G-CSFROE, which directly led to increased TEM; moreover, PKCa expression was negatively regulated by ICAM1 expression, leading to aberrant leukocyte TEM. Altogether, the ICAM1‒PKCa axis was found a meaningful target in the leukocyte TEM induced by G-CSFR upregulation.

Causal relationships between the gut microbiota, inflammatory cytokines, and alcoholic liver disease: a Mendelian randomization analysis.

Previous studies have suggested a potential association between gut microbiota and the development of alcohol-related liver disease (ALD). However, the causal relationship between gut microbiota and ALD, as well as the role of inflammatory cytokines as mediators, remains unclear. This study aims to explore the causal relationship between gut microbiota and ALD using Mendelian randomization (MR) methods, and to analyze the mediating role of inflammatory cytokines. Gut microbiota, 91 inflammatory cytokines, and ALD were identified from summary data of large-scale genome-wide association studies (GWAS). MR was employed to investigate the causal relationship between gut microbiota, cytokines, and ALD, with the inverse variance-weighted method (IVW) as the primary statistical approach. Additionally, we examined whether inflammatory cytokines act as mediating factors in the pathway from gut microbiota to ALD. The IVW results confirmed two positive and one negative causal effect between genetic liability in the gut microbiota and ALD. Escherichia coli (P= 0.003) was identified as a protective factor for ALD, while Roseburia hominis (P=0.023) and Family Porphyromonadaceae (P=0.038) were identified as risk factors for ALD. Furthermore, there were five positive and two negative causal effects between inflammatory cytokines and ALD, with CUB domain-containing protein 1 (P= 0.035), Macrophage colony-stimulating factor 1 (P=0.047), Cystatin D (P = 0.035), Fractalkine (P=0.000000038), Monocyte chemoattractant protein-1 (P=0.004) positively associated with ALD onset. CD40L receptor (P= 0.044) and Leukemia inhibitory factor (P = 0.024) exhibited protective effects against ALD. Mediation MR analysis indicated that CUB domain-containing protein 1 (mediation proportion=1.6%, P=0.035), Cystatin D (mediation proportion=1.5%, P=0.012), and Monocyte chemoattractant protein-1 (mediation proportion=3.3%, P=0.005) mediated the causal effect of Roseburia hominis on ALD. In conclusion, our study supports a causal relationship among gut microbiota, inflammatory cytokines and ALD, with inflammatory cytokines potentially acting as mediating factors in the pathway from gut microbiota to ALD.

Acute and chronic impact of interleukin-33 stimulation on chemokines and growth factors in human cord blood-derived mast cells.

Mast cells (MCs) are multifaceted immune cells that are capable of recognizing and responding to various stimuli by releasing an array of cytokines. We aimed to use human cord blood-derived mast cells (hCBMCs) as a model to evaluate different conditions under which chemokines and growth factors are expressed and secreted as mediators upon stimulation with the alarmin interleukin-33 (IL-33). hCBMCs were stimulated with 10 ng/mL or 20 ng/mL of recombinant human IL-33 (rhIL-33) for 6 h (acute) or 24 h (chronic). The mRNA expression of chemokines and growth factors was analyzed using microarrays, and the mediators released in the supernatant were evaluated using a multiplex assay. The mRNA expression levels of C-C chemokine ligands (CCL) CCL1, CCL5, granulocyte macrophage colony-stimulating factor (GM-CSF), and macrophage inflammatory protein (MIP)-4/CCL18 were upregulated under all conditions. In contrast, C-X-C motif chemokine ligand (CXCL) CXCL8 and CCL24 levels increased only under acute (6 h) and prolonged (24 h) conditions, respectively. Moreover, high levels of CXCL8, MIP-1α, and MIP-1β were secreted during acute inflammation, whereas the release of GM-CSF and CXCL9 proteins increased under all four conditions. This study highlights the sentinel role of MCs in mounting a specific immune response against a pathogenic-like stimulus in a timely and dose-dependent manner and is relevant for improving inflammatory treatment options.

Insights into CSF-1R Expression in the Tumor Microenvironment.

The colony-stimulating factor 1 receptor (CSF-1R) plays a pivotal role in orchestrating cellular interactions within the tumor microenvironment (TME). Although the CSF-1R has been extensively studied in myeloid cells, the expression of this receptor and its emerging role in other cell types in the TME need to be further analyzed. This review explores the multifaceted functions of the CSF-1R across various TME cellular populations, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), endothelial cells (ECs), and cancer stem cells (CSCs). The activation of the CSF-1R by its ligands, colony-stimulating factor 1 (CSF-1) and Interleukin-34 (IL-34), regulates TAM polarization towards an immunosuppressive M2 phenotype, promoting tumor progression and immune evasion. Similarly, CSF-1R signaling influences MDSCs to exert immunosuppressive functions, hindering anti-tumor immunity. In DCs, the CSF-1R alters antigen-presenting capabilities, compromising immune surveillance against cancer cells. CSF-1R expression in CAFs and ECs regulates immune modulation, angiogenesis, and immune cell trafficking within the TME, fostering a pro-tumorigenic milieu. Notably, the CSF-1R in CSCs contributes to tumor aggressiveness and therapeutic resistance through interactions with TAMs and the modulation of stemness features. Understanding the diverse roles of the CSF-1R in the TME underscores its potential as a therapeutic target for cancer treatment, aiming at disrupting pro-tumorigenic cellular crosstalk and enhancing anti-tumor immune responses.

Impact of Neutropenia on Clinical Outcomes after Lung Transplantation.

Neutropenia is a frequent complication among solid organ transplant (SOT) recipients receiving immunosuppressive therapy and antimicrobial prophylaxis. However, there are limited studies analysing the frequency and impact of neutropenia in lung transplant recipients (LTRs). Our aim was to analyse the frequency of neutropenia, the need for granulocyte colony-stimulating factor (GCSF) treatment within the first 18 months post-transplant and its association with acute rejection, chronic lung allograft dysfunction (CLAD), overall survival and the development of infections. This observational and retrospective study recruited 305 patients who underwent lung transplantation between 2009 and 2019, with outpatient quarterly follow-up during the first 18 months post-surgery. During this period, 51.8% of patients experienced at least one episode of neutropenia. Neutropenia was classified as mild in 50.57% of cases, moderate in 36.88% and severe in 12.54%. GCSF treatment was indicated in 23.28% of patients, with a mean dose of 3.53 units. No statistically significant association was observed between neutropenia or its severity and the development of acute rejection, CLAD or overall survival. However, the patients who received GCSF treatment had a higher mortality rate compared to those who did not. Sixteen patients (5.25%) developed infections during neutropenia, with bacterial infections being the most common. Neutropenia is common in the first 18 months after lung transplantation and most episodes are mild. We did not find an association between neutropenia and acute rejection, CLAD, or mortality. However, the use of GCSF were associated with worse post-transplant survival.

ACUTE EOSINOPHILIC APPENDICITIS IN A CHILD WITH NORMAL TOTAL LEUKOCYTE COUNT AND ABSOLUTE EOSINOPHILIC COUNT

Abstract Introduction/Objective Eosinophilic appendicitis is a rare condition with a reported incidence of 0.03% to 1.2%, and often presents with clinical manifestations indistinguishable from acute appendicitis. Eosinophilic appendicitis may be associated with a localized allergic phenomenon. Methods/Case Report We present a 13-year-old male with ~24-hour history of constipation who was brought to the emergency department because of right lower quadrant abdominal pain, nausea, and vomiting. He was afebrile and had no antecedent of atopy or parasitic infestation. Laboratory investigation revealed an elevated C-reactive protein: 0.7 mg/dL [0.0-0.3]; mildly decreased hemoglobin: 12.2 g/dL [12.6 -16.8]; normal white blood cell count: 9.7 x10 3/mcL [3.2-10.6]; eosinophil count:1.7% [&amp;lt;5] and mildly elevated monocyte count: 0.9 x103/mcL [0.2-0.7]. Ultrasound examination revealed a non-compressible 7mm in diameter hyperemic appendix. The laparoscopic appendectomy specimen measured 9.5 cm long by 0.8 cm in diameter. The serosa was focally congested and there was mild mural thickening but no obvious sign of active appendicitis. Microscopic examination showed focally abundant mucosal eosinophils and a considerable sprinkling of eosinophils throughout the muscularis propria. No intraluminal parasite or neutrophilic associated mucosal damage was seen. The final diagnosis was: Acute Eosinophilic Appendicitis. Results (if a Case Study enter NA) N/A Conclusion Among the many and still intriguing causes of appendicitis is acute eosinophilic appendicitis. Eosinophils exert homeostatic roles in the normal host and pathological eosinophil-mediated processes over different tissues and their varied milieu. While this patient did not have any evidence of allergy, parasitic infestation, or elevated eosinophilic count in his work up, the presentation of acute appendicitis without an increase in total leukocytic count may alert for the possibility of an eosinophilic appendicitis. Conceivably, eosinophil mediators, such as IL-5, IL-33, granulocyte–macrophage colony-stimulating factor, thymic stromal lymphopoietin, and eotaxin-1 determine eosinophil behavior in a rarified appendix microenvironment.

Granulocyte colony-stimulating factor for stem cell mobilisation in acute myocardial infarction: a randomised controlled trial

BackgroundTo determine whether granulocyte colony-stimulating factor (G-CSF) improves clinical outcomes after large ST-elevation myocardial infarction (STEMI) when administered early in patients with left ventricular (LV) dysfunction after successful percutaneous coronary...

Clinical features, treatment, and outcome of granulocyte colony stimulating factor-induced sweet syndrome.

Sweet syndrome (SS) is a rare dermatological adverse reaction caused by granulocyte colony-stimulating factor (G-CSF), but the characteristics of G-CSF-induced SS are unclear. This study aims to elucidate the characteristics of G-CSF-induced SS and offer guidance for its prevention and management. We collected relevant case reports of G-CSF-induced SS by searching pertinent databases until June 30, 2024, and synthesized the data for retrospective analysis. A total of fifty patients were analyzed, with a median age of 44 years (1.7-77). The onset of SS occurred between 2 and 90 days post-administration, with a median onset time of 7 days. The predominant cutaneous manifestations included papules/plaques (74.0%), nodules (32.0%), and vesicles/bullae (24.0%). Fever presented in 74.0% of cases, while extra-cutaneous symptoms appeared in 32% of patients. Skin biopsy revealed key findings such as dermal diffuse neutrophil infiltration (97.8%), leukocytoclasis (19.1%), and dermal papillary edema (27.7%). Following both the cessation of G-CSF and systemic corticosteroids treatment, patients showed symptomatic improvement at a median interval of 7 days (2-70). Clinicians should remain vigilant for the risk of SS during G-CSF administration. Skin biopsy plays a crucial role in confirming SS diagnosis. G-CSF-induced SS exhibits a favorable response to corticosteroids, and re-administration of G-CSF should be avoided due to the risk of symptom recurrence.

Granulocyte colony-stimulating factor protects against arthritogenic alphavirus pathogenesis in a type I IFN-dependent manner.

Arthritogenic alphaviruses cause disease characterized by fever, rash, and incapacitating joint pain. Alphavirus infection stimulates robust inflammatory responses in infected hosts, leading to the upregulation of several cytokines, including granulocyte colony-stimulating factor (G-CSF). G-CSF is secreted by endothelial cells, fibroblasts, macrophages, and monocytes and binds to colony stimulating factor 3 receptor (CSF3R, also known as G-CSFR) on the surface of myeloid cells. G-CSFR signaling initiates proliferation, differentiation, and maturation of myeloid cells, especially neutrophils. Importantly, G-CSF has been found at high levels in both the acute and chronic phases of chikungunya disease; however, the role of G-CSF in arthritogenic alphavirus disease remains unexplored. Here, we sought to test the effect of G-CSF on chikungunya virus (CHIKV) and Mayaro virus (MAYV) infection using G-CSFR-deficient mice (G-CSFR-/-). We observed sustained weight loss in G-CSFR-/- mice following viand MAYV infection compared to wild-type mice. Furthermore, G-CSFR-/- mice had a significantly higher percentage of inflammatory monocytes and reduction in neutrophils throughout infection. The difference in weight loss in G-CSFR-/- mice induced by alphavirus infection was corrected by blocking type I IFN signaling. In summary, these studies show that type I IFN signaling contributes to G-CSFR mediated control of arthritogenic alphavirus disease.

Molecular Signaling Pathways and MicroRNAs in Bone Remodeling: A Narrative Review.

Bone remodeling is an intricate process executed throughout one's whole life via the cross-talk of several cellular events, progenitor cells and signaling pathways. It is an imperative mechanism for regaining bone loss, recovering damaged tissue and repairing fractures. To achieve this, molecular signaling pathways play a central role in regulating pathological and causal mechanisms in different diseases. Similarly, microRNAs (miRNAs) have shown promising results in disease management by mediating mRNA targeted gene expression and post-transcriptional gene function. However, the role and relevance of these miRNAs in signaling processes, which regulate the delicate balance between bone formation and bone resorption, are unclear. This review aims to summarize current knowledge of bone remodeling from two perspectives: firstly, we outline the modus operandi of five major molecular signaling pathways, i.e.,the receptor activator of nuclear factor kappa-B (RANK)-osteoprotegrin (OPG) and RANK ligand (RANK-OPG-RANKL), macrophage colony-stimulating factor (M-CSF), Wnt/β-catenin, Jagged/Notch and bone morphogenetic protein (BMP) pathways in regards to bone cell formation and function; and secondly, the miRNAs that participate in these pathways are introduced. Probing the miRNA-mediated regulation of these pathways may help in preparing the foundation for developing targeted strategies in bone remodeling, repair and regeneration.

LncRNA MEG3 suppresses hepatocellular carcinoma by stimulating macrophage M1 polarization and modulating immune system via inhibiting CSF-1 in vivo/vitro studies

Hepatocellular carcinoma (HCC) is characterized by a complex tumor microenvironment (TME), and long non-coding RNAs (lncRNAs) MEG3 emerged as regulators of macrophage polarization with a negative relationship with colony-stimulating factor 1 (CSF-1). Few studies are on the interplay among MEG3, CSF-1, T helper cells (Th), and the programmed cell death protein 1 and its ligands (PD-1/PD-Ls) in TME of HCC.MEG3 expression in THP-1 macrophages, monitored polarization, and PD-1/PD-Ls expression were through flow cytometry, WB, and RT-qPCR. In co-cultures, the interaction of MEG3, macrophage, and HCC was assayed by ELISA. The invasive and migratory of HCC were assessed through experiments such as CCK-8, clonogenic assay, wound healing, and Transwell. A xenograft mouse model of HCC was established, administered with MEG3 overexpression (OE) or knockdown (KD) constructs, and monitored tumor growth. In vitro, MEG3 OE induced a robust M1 macrophage phenotype, evidenced by elevated expression of M1 markers and a significant increase in Th1 cytokines, with a concomitant decrease in Th2 cytokines. This was paralleled by reduced CSF-1 and PD-1/PD-Ls expression. In contrast, MEG3 KD promoted an M2 phenotype with increased CSF-1 and PD-1/PD-Ls expression, and an upregulation of Th2 cytokines. MEG3 OE inhibited the growth, invasion, and migration of HCC, while the opposite was observed when MEG3 was downregulated. In vivo, MEG3 OE resulted in significantly reduced tumor growth, with decreased PD-1/PD-Ls expression on macrophages and enhanced Th1 response. Conversely, MEG3 KD promoted tumor growth with increased PD-1/PD-Ls and a Th2-skewed immune response. MEG3 modulates the TME by affecting TAMs through CSF-1, thereby influencing the balance of Th1/Th2 cells and altering the expression of PD-1/PD-L1s. This study demonstrates that targeting MEG3 is an effective therapeutic strategy for HCC.

Exploring causal correlations between inflammatory cytokines and coronary heart disease: A Mendelian randomization study.

Coronary heart disease (CHD) is a global health concern, with inflammation significantly contributing to its pathogenesis. It is crucial to understand the relationship between inflammatory cytokines and CHD. This study investigates the causal correlations between circulating inflammatory cytokines and CHD using Mendelian randomization (MR), assessing both causative and resultant roles of these cytokines in CHD. In this bidirectional MR analysis, we used genetic data from a genome-wide association study (GWAS) of 60,801 CHD cases and 123,504 controls of European ancestry. We derived inflammatory cytokine data from a GWAS summary of 14,824 participants. The primary analytical approach was the inverse variance-weighted (IVW) method, supported by MR-Egger, weighted median, and weighted mode analyses. Heterogeneity was assessed using the Cochrane Q test, and horizontal pleiotropy was evaluated through the MR-Egger intercept and the MR-PRESSO global test, ensuring robustness against potential pleiotropic bias. This study pinpointed several cytokines as key upstream influencers on the risk of CHD, including eotaxin (CCL11) (odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.03-1.18, P = .003), C-C motif chemokine ligand 20 (CCL20) (OR: 1.15, 95% CI: 1.05-1.25, P = .002), macrophage colony-stimulating factor 1 (CSF1) (OR: 1.09, 95% CI: 1.01-1.17, P = .020), Fibroblast growth factor 21 (FGF21) (OR: 1.14, 95% CI: 1.01-1.29, P = .038), Fms-related tyrosine kinase 3 ligand (FLT3LG) (OR: 1.26, 95% CI: 1.09-1.44, P = .001), neurotrophin-3 (NT-3) (OR: 1.12, 95% CI: 1.01-1.24, P = .026), and leukemia inhibitory factor (LIF) (OR: 0.89, 95% CI: 0.80-0.99, P = .029). Conversely, T-cell surface glycoprotein CD5 (CD5) (beta: -0.15, 95% CI: -0.29 to -0.01, P = .042) were identified as downstream factors impacted by CHD. No evidence of heterogeneity or horizontal pleiotropy was detected across all results, and a leave-one-out analysis substantiated the robustness of these findings. These findings suggest that CCL11, CCL20, CSF1, FGF21, FLT3LG, NT-3, and LIF may play a crucial role in the pathogenesis of CHD. Additionally, CHD may impact the expression of CD5. Additional research is needed to explore the potential of these biomarkers in the prevention and treatment of CHD.

Methotrexate promotes the release of granulocyte–macrophage colony-stimulating factor from rheumatoid arthritis fibroblast-like synoviocytes via autocrine interleukin-1 signaling

BackgroundActivated fibroblast-like synoviocytes (FLS) are drivers of synovitis and structural joint damage in rheumatoid arthritis (RA). Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators.MethodsPrimary RA-FLS were activated by stimulation with interleukin-1β (IL-1β) or platelet-derived growth factor + IL-1β in the presence or absence of MTX or TOFA, with or without additional inhibitors. Co-cultures of synovial cells were performed in direct and indirect systems. Cells were collected for RNA sequencing or qPCR, and supernatants were analyzed for protein concentrations.ResultsSix thousand three hundred fifty genes were differentially expressed, the majority being upregulated, in MTX-treated activated RA-FLS and 970 genes, the majority being downregulated, in TOFA-treated samples. Pathway analysis showed that MTX had largest effects on ‘Molecular mechanisms of cancer’ and TOFA on ‘Interferon signaling’. Targeted analysis of disease-associated genes revealed that MTX increased the expression of cell cycle-regulating genes but also of pro-inflammatory mediators like IL-1α (IL1A) and granulocyte–macrophage colony-stimulating factor, GM-CSF (CSF2). The MTX-promoted expression of CSF2 in activated RA-FLS peaked at 48 h, could be mediated via either NF-κB or AP-1 transcription factors, and was abrogated by IL-1 inhibitors (IRAK4 inhibitor and anakinra). In a co-culture setting, MTX-treatment of activated RA-FLS induced IL1B expression in macrophages.ConclusionsMTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.

Proinflammatory microglial activation impairs invitro cortical tissue repair via zinc-dependent ADAM17 cleavage of the CSF-1 receptor.

Infection and subsequent inflammatory processes negatively impact prognosis in individuals with traumatic brain injury (TBI). Tissue repair following TBI is tightly regulated by microglia, promoting or, importantly, preventing astrocyte-mediated repair processes, depending on the activation state of the neuroimmune cells. This study investigated the poorly understood mechanism linking proinflammatory microglia activation and astrocyte-mediated tissue repair using an invitro mechanical injury model in mixed cortical cultures of rat neurons and glia. We hypothesized that proinflammatory activation disrupts the microglial response to colony-stimulating factor 1 (CSF-1), which stimulates microglia migration and proliferation, both essential for astrocyte-mediated tissue repair. Following mechanical damage, cultures were treated with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) to induce a proinflammatory state. Immunocytochemical and biochemical analyses were used to evaluate glial repair. Proinflammatory activation dramatically impeded wound closure, reducing microglial levels via upregulation of the zinc-dependent disintegrin and metalloprotease 17 (ADAM17), leading to the cleavage of the CSF-1 receptor (CSF-1R). Indeed, pharmacological inhibition of ADAM17 effectively promoted wound closure during inflammation. Moreover, zinc chelation prevented ADAM17-mediated cleavage of CSF-1R and induced the release of trophic factors, dramatically improving tissue recovery. Our findings strongly identify ADAM17 as a primary regulator of CSF-1R-mediated signaling and establish a mechanism defining the association between pro-inflammatory microglial activation and tissue repair following injury.

Distinct immune profiles and clinical outcomes in sepsis subphenotypes based on temperature trajectories.

Sepsis is a heterogeneous syndrome. Identification of sepsis subphenotypes with distinct immune profiles could lead to targeted therapies. This study investigates the immune profiles of patients with sepsis following distinct body temperature patterns (i.e., temperature trajectory subphenotypes). Hospitalized patients from four hospitals between 2018 and 2022 with suspicion of infection were included. A previously validated temperature trajectory algorithm was used to classify study patients into temperature trajectory subphenotypes. Microbiological profiles, clinical outcomes, and levels of 31 biomarkers were compared between these subphenotypes. The 3576 study patients were classified into four temperature trajectory subphenotypes: hyperthermic slow resolvers (N = 563, 16%), hyperthermic fast resolvers (N = 805, 23%), normothermic (N = 1693, 47%), hypothermic (N = 515, 14%). The mortality rate was significantly different between subphenotypes, with the highest rate in hypothermics (14.2%), followed by hyperthermic slow resolvers 6%, normothermic 5.5%, and lowest in hyperthermic fast resolvers 3.6% (p < 0.001). After multiple testing correction for the 31 biomarkers tested, 20 biomarkers remained significantly different between temperature trajectories: angiopoietin-1 (Ang-1), C-reactive protein (CRP), feline McDonough sarcoma-like tyrosine kinase 3 ligand (Flt-3l), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-15, IL-1 receptor antagonist (RA), IL-2, IL-6, IL-7, interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), human macrophage inflammatory protein 3 alpha (MIP-3a), neutrophil gelatinase-associated lipocalin (NGAL), pentraxin-3, thrombomodulin, tissue factor, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), and vascular cellular adhesion molecule-1 (vCAM-1).The hyperthermic fast and slow resolvers had the highest levels of most pro- and anti-inflammatory cytokines. Hypothermics had suppressed levels of most cytokines but the highest levels of several coagulation markers (Ang-1, thrombomodulin, tissue factor). Sepsis subphenotypes identified using the universally available measurement of body temperature had distinct immune profiles. Hypothermic patients, who had the highest mortality rate, also had the lowest levels of most pro- and anti-inflammatory cytokines.

Two homologous genes encoding interleukin (IL)-34 in the common carp (Cyprinus carpio L.): Roles in inflammatory modulation and anti-bacterial defense

In mammals, interleukin 34 (IL-34) is a ligand for macrophage colony-stimulating factor receptor (M-CSFR), promoting inflammatory responses and inducing the synthesis and secretion of various cytokines. However, studies on its function in lower vertebrates is limited, and its evolutionary relationship with homologous molecules in mammals remains unclear. In this study, two IL-34-encoding genes were cloned and identified in common carp (Cyprinus carpio L.), designated as CcIL-34A and CcIL-34B, with an amino acid sequence similarity of 77.7 %. Gene synteny analysis revealed that the IL-34 gene loci are relatively conserved, and both are located downstream of SF3B3. The expression patterns of CcIL-34s were analyzed using qRT-PCR, and this showed that they are expressed across all tested tissues, with higher levels in the liver, spleen, and head kidney and lower levels in the gills and intestines. Following infection with Aeromonas hydrophila, the mRNA expression levels of CcIL-34s in the gills, head kidney, intestines, and spleen were significantly upregulated. Immunofluorescence was also employed to assess changes in CcIL-34 protein expression, showing a significant increase in carp spleens 24 h after A. hydrophila infection, suggesting that CcIL-34s contribute to host defense against this bacterium. To investigate the immunological function of IL-34 in vivo, pc-CcIL-34A and pc-CcIL-34B eukaryotic expression plasmids were constructed and injected intramuscularly into fish. Five days after injection, the expression levels of inflammation-related cytokines in the head kidney and spleen were significantly altered. Furthermore, 24 h post-A. hydrophila infection, the bacterial loads in the liver, spleen, and kidneys were significantly reduced. Ten days post-infection, the survival rates in the groups with CcIL-34A and CcIL-34B overexpression were 40 % and 36.7 %, respectively, compared to 16.7 % in the control group. These findings suggest that CcIL-34s are involved in modulating inflammatory responses, enhancing the immune response, and improving survival rates in fish following bacterial infection, thus supporting the potential use of IL-34 molecules in aquaculture.

Clinical effect of prophylactic pegfilgrastim in patients with newly diagnosed acute lymphoblastic leukemia who receive intensive chemotherapy.

Using granulocyte colony-stimulating factor (G-CSF) after completing chemotherapy reduces the duration of neutropenia and infections. However, the efficacy and safety of prophylactic pegfilgrastim in acute lymphoblastic leukemia (ALL) patients have not yet been evaluated after intensive cytotoxic chemotherapy compared to the daily G-CSF. This study aimed to evaluate the efficacy of pegfilgrastim for ALL patients who received intensive chemotherapy compared with a short-acting G-CSF. Clinical data of 145 patients treated with hyper-CVAD, modified VPDL/VPD, or KALLA 1406/1407 regimen were retrospectively evaluated. Pegfilgrastim or the short-acting G-CSF was selected according to the clinician's discretion. Patients not receiving pegfilgrastim were treated with the short-acting G-CSF. The median age of enrolled patients was 45years. Sixty newly diagnosed ALL patients were treated with hyper-CVAD regimen, while KALLA and VPDL regimens were administered to 39 and 46 patients, respectively. Among the 60 patients treated with hyper-CVAD, 20 patients received pegfilgrastim. Patients who received pegfilgrastim had a significantly shorter duration of neutropenia and hospitalization and reduced incidence of severe infections compared to patients receiving the short-acting G-CSF. Consistent results were also confirmed in an analysis targeting only patients who achieved remission during hyper-CVAD induction therapy. There was no significant difference in neutrophil recovery ability and hospitalization duration when the daily short-acting G-CSF was used prophylactically after completing hyper-CVAD, KALLA, and VPDL regimens as induction therapy. Using pegfilgrastim after hyper-CVAD therapy was more effective than the short-acting G-CSF in terms of infection, neutropenia recovery, and hospitalization in patients with newly diagnosed ALL.

Exploring Causal Correlations Between Inflammatory Cytokines and Kawasaki Disease: A Mendelian Randomization

Background The role of inflammatory cytokines in Kawasaki disease (KD) pathogenesis is known, but causal relationships are unclear. This study investigates these connections using Mendelian randomization (MR). Methods Genetic variations associated with KD were obtained from a GWAS including 119 cases and 6071 controls of European ancestry. Genetic data on inflammatory cytokines were sourced from a GWAS of 8,293 healthy participants. Results The study identified significant associations between higher levels of macrophage colony stimulating factor (M-CSF), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and increased risk of KD. The odds ratios (OR) were 1.04 (95% CI: 1.01–1.08, p = 0.010) for M-CSF, 1.03 (95% CI: 1.01–1.05, p = 0.026) for MCP-1, and 1.02 (95% CI: 1.01–1.04, p = 0.027) for TRAIL. Conclusion This study suggests that M-CSF, MCP-1, and TRAIL are potentially involved in the etiology of KD.

Association of Granulocyte Colony-Stimulating Factor Treatment with Risk of Brain Metastasis in Advanced Stage Breast Cancer.

The routine use of granulocyte colony-stimulating factor (GCSF) is not recommended for the prevention or treatment of chemotherapy-induced neutropenia or febrile neutropenia because risks associated with certain types of cancers, distant organ metastases, and primary tumor growth cannot be excluded. We examined the association between GCSF use and the incidence of brain metastasis (BM), as well as BM-free survival (BMFS). This retrospective cohort study included 121 stage IV breast cancer patients without confirmed BM at the time of diagnosis and who received at least one course of systematic chemotherapy or target therapy at a tertiary teaching hospital between 1 January 2014 and 31 December 2022. The effect of GCSF use on BM was assessed with other confounding factors in Cox regression analyses. In this retrospective cohort, patients who received GCSF treatment had a significantly higher incidence of BM than those who did not (34.9% vs. 13.8%, p = 0.011). Univariate Cox regression analysis showed that GCSF use, menopause status, hormone treatment, HER2 treatment, cumulative dosage, dosage density, and neutropenia were independent risk factors for BMFS (p < 0.05). GCSF users had a higher risk of BM (adjusted HR: 2.538; 95% CI: 1.127-5.716, p = 0.025) than nonusers. BM risk was significantly associated with those with neutropenia (RR: 1.84, 95% CI: 1.21, 2.80) but not with those without neutropenia (RR: 0.59, 95% CI: 0.41-0.84, Interaction p-value < 0.05). The higher the dose density of GCSF, the higher the risk compared with those who do not use GCSF (p for trend < 0.01). These preliminary results suggest that GCSF is associated with BM in patients with stage IV breast cancer who did not have BM at initial diagnosis. Further comprehensively designed large-scale observational studies are needed to confirm our preliminary results.

7245 A case of refractory methimazole-induced agranulocytosis treated with high-dose G-CSF

Abstract Disclosure: S. Shah: None. D. Mathur: None. G. Bao: None. S. Shah: None. D.M. Antoniucci: None. Case Presentation: Despite their efficacy in treating hyperthyroidism, antithyroid drugs (ATDs) carry a rare risk of life-threatening agranulocytosis (ANC &amp;lt;500/μL), with incidence varying from 0.1 to 0.4%. Patients with agranulocytosis may benefit from granulocyte-colony stimulating factor (G-CSF) to shorten recovery and reduce hospitalization costs. We present the case of a 37-year-old woman with Graves disease, who developed methimazole (MMZ)-induced agranulocytosis and was treated with high-dose G-CSF. At diagnosis, MMZ 10 mg BID was started and later reduced to 5 mg BID. After 2 months, she presented to the ED with a dental infection, an arm abscess after a cat scratch, and fevers. Blood-work showed WBC of 1500/μL, ANC of 0/μL, and rare granulocytes on manual differential. Flow cytometry did not show clonal lymphoid or blast populations. MMZ was stopped and antibiotics were started. Her hyperthyroidism was managed with propranolol and iodine solution in anticipation of definitive thyroidectomy. On day 4 of admission, tbo-filgrastim 450 mcg daily injections were started for persistent neutropenia. Despite 3 doses of G-CSF, ANC remained at 0/μL, prompting a bone marrow biopsy that showed no dysplastic or aplastic phenotype. After 9 doses of G-CSF up to 600 mcg daily, ANC fully recovered on day 14. She underwent thyroidectomy, and 2 months later her ANC and thyroid hormone levels were within normal. Discussion: This report illustrates a case of severe, refractory ATD-induced agranulocytosis and highlights the utility of G-CSF in treating high risk patients. Classically, ATD-induced agranulocytosis occurs in those aged &amp;gt;65 years, follows high dose therapy, and occurs within 60 days of treatment initiation. G-CSF is often used in clinical practice, although its efficacy is not well established. A recent meta-analysis demonstrated that G-CSF can hasten recovery by 3 days. Other studies report no difference or prolonged agranulocytosis up to 14 days despite G-CSF, especially in patients with ANC &amp;lt;100/μL. Whether this is a lack of true benefit or inadequate dosing is unclear. This case reviews the use of high dose G-CSF in a patient with profound neutropenia. Prompt ANC recovery was crucial given neutropenic fevers and need for thyroidectomy. Even with escalating doses of G-CSF, her ANC required 14 days to recover - twice the typical length of recovery. Whether G-CSF impacted the time course of her recovery is difficult to discern. Identifying the mechanisms underlying ATD induced agranulocytosis may explain delayed responses to G-CSF. Notably, the 2016 ATA guidelines do not incorporate G-CSF into ATD-induced agranulocytosis management. This conservative approach reflects a paucity of evidence supporting G-CSF use. Further research must investigate underlying mechanisms and clarify indications for G-CSF use to improve outcomes and reduce costs of care. Presentation: 6/1/2024