Journal of Leukocyte Biology最新文献

Neutrophil extracellular traps have been increasingly recognized as important modulators of tumor immunity. In this study, we investigated the prognostic significance of neutrophil extracellular trap-related genes expression and their impact on tertiary lymphoid structures in lung adenocarcinoma. Using transcriptomic data from The Cancer Genome Atlas and Gene Expression Omnibus cohorts, we identified 4 neutrophil extracellular trap-associated molecular subtypes and developed a robust 13-gene neutrophil extracellular trap-related prognostic signature via Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. High-risk patients exhibited significantly worse overall survival, higher Tumor Immune Dysfunction and Exclusion (TIDE) and exclusion scores, and decreased cytotoxic activity and tertiary lymphoid structure signatures. Immunohistochemistry of 68 lung adenocarcinoma specimens further validated that high myeloperoxidase expression (a marker of neutrophil extracellular traps) correlated with lower tertiary lymphoid structure density and reduced tertiary lymphoid structure maturation, as indicated by reduced CD21 and BCL6 expression. Functional enrichment and immune infiltration analyses revealed that neutrophil extracellular trap-high tumors were associated with suppressive immune phenotypes, metabolic reprogramming, and impaired lymphoid chemokine expression (eg CCL19, CXCL13). Our findings suggest that neutrophil extracellular traps not only predict poor prognosis in lung adenocarcinoma but may also impair tertiary lymphoid structure maturation and local antitumor immunity, highlighting their potential as therapeutic targets.

Relapse and therapy resistance remain major barriers to improving clinical outcomes in acute myeloid leukemia (AML), underscoring the need for actionable therapeutic targets. In this study, we identify calcium/calmodulin-dependent protein kinase II delta (CaMKIIδ) as a novel vulnerability in AML. CaMKIIδ is aberrantly overactivated in primary and relapse/refractory (R/R) AML patient samples compared to healthy donor peripheral blood mononuclear cells, with elevated expression correlating with increased tumor burden and inferior survival. Mechanistically, CaMKIIδ inhibition induces rapid apoptosis in AML bulk and stem/progenitor cells by suppressing STAT3 phosphorylation, downregulating CDK6-mediated cell cycle progression, and reducing BCL-2-dependent survival. Strikingly, pharmacological blockade of CaMKIIδ using the small-molecule inhibitor hesperadin effectively eliminates AML cells in vitro and achieves sustained disease regression in AML xenograft mouse models. Our findings establish CaMKIIδ as a central regulator of AML cell survival and apoptosis, providing a preclinical rationale for targeting CaMKIIδ to overcome therapy resistance in AML.

Sjögren's disease (SjD) is a systemic autoimmune disease. The underlying disease mechanisms remain poorly understood and there are no curative therapies. MyD88-mediated signaling is essential for SjD, although the pathways that rely on MyD88 are not well characterized. Our objective was to determine if MyD88-dependent IL-1 cytokines mediate inflammation in SjD. Using a SjD mouse model and patient samples, RNA-sequencing was performed on salivary tissue and peripheral B cells. Splenocytes from SjD mice were stimulated with IL-36 cytokines and B cell activation was assessed. Finally, ELISAs were employed to measure IL-36 in SjD patient sera. Our data revealed that IL-1 family-associated genes were dysregulated in SjD salivary tissue. Salivary B cells showed upregulation of genes associated with MyD88 and IL-36 activation and peripheral B cells from SjD mice had dysregulated IL-1 signaling networks. Moreover, B cells from SjD mice showed enhanced activation when stimulated with IL-36 cytokines, and splenocytes derived from SjD mice exhibited elevated cytokine secretion. Finally, high levels of IL-36α and IL-36γ were present in SjD patient sera and IL-36α levels discriminated SjD patients from non-SjD controls. Therefore, IL-36 contributes to disease and drugs targeting IL-1 cytokines, particularly IL-36, may represent novel therapeutic targets for SjD.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing anti-tumor immunity, but their use is frequently complicated by immune-related adverse events (irAEs), particularly ICI-induced diarrhea and colitis. Growing evidence suggests that RNA-binding proteins (RBPs), which are critical post-transcriptional regulators of immune responses, may play a pivotal role in inflammatory diseases. To systematically investigate the involvement of RBPs in ICI-induced colitis, we performed a comprehensive re-analysis of published single-cell RNA sequencing (scRNA-seq) data from CD45+ immune cells isolated from ICI colitis patients, ICI-treated non-colitis patients, and healthy controls. Our analysis revealed distinct, cell-type-specific RBP expression patterns across immune cell populations, with several RBP clusters (e.g., R4 in innate lymphoid cells (ILCs) and T cells, R5 in T cells, R8 in IgA+ plasma B cells, and R10 in B cells) being uniquely enriched in ICI colitis samples, suggesting their potential involvement in colitis pathogenesis. Further subpopulation analysis identified ICI colitis-deregulated RBPs: RPL26 was markedly downregulated in both ILCs and T cells from ICI colitis patients, while PCBP2, ISG20, HSPA1A and HSPA1B were upregulated in T cells. A colitis-specific RBP cluster was identified in B cells, among which ISG20 and ZFP36L2 showed elevated expression in specific subpopulations from colitis patients. ZFP36L2 potentially targets CD83 and JUNB, as their expression decreased in mouse germinal center B cells upon ZFP36L2 knockout. These findings highlight the regulatory role of RBPs in ICI-induced colitis and identify cell-type-specific alterations that may drive disease progression. Importantly, we pinpoint immune checkpoint-related RBPs as potential therapeutic targets, offering new strategies to manage this clinically significant irAE.

Eosinophils (EOS), named after the Greek dawn goddess Eos, are multifunctional granulocytes with roles surpassing their well-established involvement in allergic diseases and parasitic infections. Herein, we highlighted the recent advancements in understanding the cellular structure, lineage development, surface receptors, and diverse phenotypes of EOS. In particular, we focused on their emerging roles in the tumor microenvironment and type 1 inflammatory responses. Additionally, we explored the cytokine signaling and transcription factor networks governing the differentiation of EOS, emphasizing the interplay among IL-5, IL-33, and GM-CSF. Notably, EOS exhibit phenotypic plasticity, with the ability to polarize into type 1 (E1) and type 2 (E2) subsets under different inflammatory conditions. This suggests their dual roles in antitumor and protumor activities. Our review underscores the potential of targeting EOS-specific receptors, including IL-5Rα and Siglec-8, for therapeutic interventions in EOS-related diseases. By combining recent findings on the metabolic milieu and interactions of EOS within complex tissue environments, we provide a comprehensive perspective on their physiological and pathological functions, paving the way for novel therapeutic strategies.

Gamma-aminobutyric acid (GABA), a non-protein component amino acid, functions as an inhibitory neurotransmitter. Here, we showed that GABA levels are significantly elevated in the bone marrow (BM) liquid of patients with multiple myeloma (MM) compared to healthy donors (HDs). Moreover, BM GABA levels correlated with key clinical parameters, including plasma cell percentage, International Staging System (ISS) stage, and immunoglobulin subtype, highlighting its association with disease severity. Mechanistically, we identified glutamic acid decarboxylase 1 (GAD1) as a critical enzyme driving intracellular GABA production in MM cells, which promotes the survival and proliferation of MM cells. Additionally, GAD1-dependent GABA production supported MM progression by activating the GABA-B receptor, as demonstrated in vitro and in vivo, underscoring the pivotal role of this receptor axis. Further mechanistic investigations revealed that the GABA-B receptor axis enhances extracellular regulated kinases1/2 (ERK1/2) activity via cAMP downregulation, facilitating MM cell survival and proliferation. Taken together, our findings establish the GABA-B receptor-ERK1/2 axis as a central regulator of MM progression and propose it as a promising target for MM therapy.

Monocytes play a fundamental role in the inflammatory response to diverse stimuli. A critical early step in the initiation of this response is the recruitment of monocytes from the bloodstream to sites of tissue injury. This migration is tightly regulated at the molecular level through interactions between vascular selectins and sialyl Lewis X (sLeX)-bearing glycoproteins on the surface of monocytes. Galectin-3, a β-galactoside-binding lectin with diverse immunological functions, has been linked to enhanced monocyte recruitment through mechanisms that are still being elucidated. Here, using a combination of genetic and pharmacological inhibition approaches, we show that galectin-3 enhances sLeX epitope biosynthesis in both mouse and human monocytes. This effect is mediated by transcriptional upregulation of α(1,3)-fucosyltransferase 7 (FUT7), a rate-limiting enzyme in sLeX synthesis. Furthermore, we demonstrate that restoring FUT7 activity in galectin-3-deficient monocytes rescues cell surface expression of sLeX. These findings reveal a previously unrecognized role for galectin-3 in regulating monocyte adhesion by directly influencing selectin ligand biosynthesis.

Patients who survive sepsis experience a prolonged period of immunosuppression. This period is accompanied by the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs), a subset of suppressive myeloid cells; however, the impact of M-MDSCs on the innate immune response to infection is not well understood. Here we investigate the effect of MDSCs on neutrophils, a critical component of the innate immune response, during bacterial infection. We found that M-MDSCs, differentiated from monocytes in vitro, impaired neutrophil chemotaxis to IL-8 in a simple microfluidic chemotactic device. We then integrated M-MDSCs and neutrophils into our 3D infection-on-a-chip device that incorporates key features of an infectious environment including an endothelial lumen, a collagen extracellular matrix, and a source of Pseudomonas aeruginosa. When M-MDSCs were present in the matrix during simulated infection with Pseudomonas aeruginosa, significantly fewer neutrophils extravasated from the lumen, and those that left traveled a shorter distance from the lumen edge. We found IL-10 secretion increased during infections in the presence of M-MDSCs and blocking IL-10 restored neutrophil extravasation, indicating IL-10 secretion reduces neutrophil extravasation in the presence of M-MDSCs. In summary, we demonstrated impaired neutrophil chemotaxis, extravasation, and migration in the presence of M-MDSCs during bacterial infection and found increased levels of IL-10 contribute to reduced extravasation, indicating that MDSCs play a role in regulating the immune environment, leading to a reduced neutrophil response to infection.

The Ets family transcription factor PU.1 plays multiple roles in hematopoiesis. PU.1 acts in a graded manner to regulate myeloid and lymphoid development with high expression levels promoting monopoiesis and low expression levels instructing B cell fate. It remains incompletely understood how PU.1 promotes monocyte development. In this study, we show that PU.1 activation upregulated, whereas PU.1 knockdown downregulated, the expression of c-Fos, Egr-1, and Egr-2, which are the immediate early response genes of the Erk1/2 pathway and have been shown to promote monopoiesis. A PU.1 mutant defective in c-Jun interaction was unable to upregulate the expression of c-Fos, Egr-1, and Egr-2, indicating that interaction with c-Jun is required for PU.1-mediated upregulation of c-Fos, Egr-1, and Egr-2. We further demonstrate that PU.1 bound to and transcriptionally activated the promoters of c-Fos, Egr-1, and Egr-2. Knockdown of c-Fos or Egr-1 favored neutrophil over monocyte development in response to PU.1 activation, which was associated with increased Gfi1 expression. Notably, PU.1-mediated upregulation of c-Fos, Egr-1, and Egr-2 was blocked upon inhibition of Erk1/2 signaling, which was also associated with an increase in Gfi1 expression and a shift toward neutrophil development at the expense of monopoiesis. Together, these results reveal a novel mechanism by which PU.1 acts to promote monopoiesis and a critical role of the Erk1/2 downstream targets c-Fos, Egr-1 and Egr-2 in PU.1-driven monocyte development.

IRGM proteins are associated with increased susceptibility to Crohn's disease, mycobacterial infections, sepsis, and other inflammatory diseases, but the cells in which they function in vivo have not been delineated. To address this, mice with conditional deletions of Irgm1 were created and challenged with model pathogens. Irgm1fl/flLyz2-Cre+ mice (a myeloid deletion) displayed marked susceptibility to infections with Salmonella typhimurium, Listeria monocytogenes, and Toxoplasma gondii, paralleling those of global Irgm1-/- mice. However, infections of Irgm1fl/flLyz2-Cre+ mice with Citrobacter rodentium showed no increase in susceptibility, contrasting with marked increases in Irgm1fl/flVav-Cre+ mice (a hematopoietic deletion). Macrophages from Irgm1fl/flLyz2-Cre+ mice displayed pathologies present in macrophages from global Irgm1-/- mice, validating the conditional deletion in myeloid cells. These results suggest that Irgm1 functioning in myeloid cells is critical for immune resistance to intracellular pathogens, while Irgm1 functioning in additional hematopoietic population(s) is required for resistance to extracellular pathogens in the intestinal lumen.