Journal of Leukocyte Biology最新文献

Myeloid cells, including monocytes, macrophages, dendritic cells, and granulocytes, constitute a versatile arm of the immune system, serving as frontline sentinels that detect and react to environmental cues and orchestrate tailored immune responses. Their ability to respond promptly to distinct threats depends on dynamic processes that include differentiation, antigen presentation, and secretion of pro-inflammatory and antimicrobial mediators. These functions are tightly linked to the integrity of the endoplasmic reticulum (ER), an essential organelle responsible for synthesis, folding, and modification of proteins. Disruption of ER homeostasis is commonly induced by infection, inflammation, autoimmunity, or cancer settings, leading to ER stress and activation of the unfolded protein response (UPR), a 3-pronged signaling pathway aiming to restore the fidelity of the cellular proteome. Among UPR branches, the inositol-requiring enzyme 1 (IRE1)/XBP1 pathway has emerged as a central regulator of myeloid cell function, integrating proteostatic stress with immune modulation. Despite growing evidence positioning the IRE1/XBP1s axis as a pivotal immunological target bearing biomedical potential, the context-dependent outcomes of this UPR branch in myeloid cells, ranging from protective to maladaptive, remain incompletely understood. In this review, we explore the multifaceted roles of IRE1 in shaping myeloid cell responses across physiological and pathological states, highlighting molecular mechanisms and their impact on immune homeostasis and disease pathogenesis.

The cytokine CSF-1 and its tyrosine kinase-encoding receptor CSF1R are important for the development and proliferation/survival of most tissue macrophages. We recently identified TNF-α-induced protein 2 (TNFAIP2) as a unique cellular regulator of CSF1R activation: TNFAIP2 increased the response of macrophages to CSF-1, which might be explained at least in part by the induction of CSF1R clustering by TNFAIP2, since CSF1R clusters accelerate CSF-1-induced CSF1R dimerization/activation. Here, we report an enhanced trafficking of CSF1R to the cell surface as an additional mechanism by which TNFAIP2 increases macrophage response to CSF-1. The mutation in the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding site of TNFAIP2 or CSF1R, or the deprivation of cellular PIP2 reduced the enhanced CSF1R trafficking by TNFAIP2, indicating the importance of PIP2-mediated membrane localization of TNFAIP2 and CSF1R. Mechanistically, a small GTPase RalA and the exocyst complex involved in vesicle trafficking were required for the enhanced CSF1R trafficking by TNFAIP2. Interestingly, the RalA-exocyst complex cascade was also required for the enhanced CSF1R clustering by TNFAIP2. Our results suggest that TNFAIP2 enhances intracellular trafficking and cluster formation of CSF1R through PIP2, RalA, and the exocyst complex, thereby increasing the macrophage response to CSF-1. Our results also suggest that TNFAIP2 regulates other receptor tyrosine kinases.

Neutrophils, the most abundant leukocytes in humans, exhibit significant differences from their murine counterparts, shaping immune responses and disease outcomes. Recent studies indicate that fungal exposure in rewilded mice modifies neutrophil development, aligning it more closely with human neutrophil characteristics and emphasizing the role of environmental cues in neutrophil ontogeny. Beyond their immune defense functions, intestinal fungi contribute to granulopoiesis, sustaining immune activation through mechanisms distinct from those observed in invasive fungal infections. This review explores the complex interplay between fungi and neutrophils, focusing on how neutrophils respond to fungal colonization and infection. We examine the influence of fungal components, such as cell wall structures and toxins, on neutrophil activation and differentiation, which ultimately dictate their immune function. Additionally, we discuss the impact of gut mycobiota on disease progression and highlight emerging therapeutic strategies that target these interactions to manage immune-related disorders effectively. Understanding these mechanisms provides new insights into immune regulation and potential treatments for conditions driven by neutrophil dysfunction.

Sepsis is a life-threatening condition driven by a dysregulated host response to infection, in which the innate immune axis-particularly the crosstalk between neutrophils and macrophages-plays a central role in dictating disease trajectory. This review delineates the functional, metabolic, and spatial characteristics of these two phagocytic cell types and highlights their bidirectional interactions across distinct immunological phases of sepsis. Multiple intercellular conduits, including extracellular vesicles, cytokine-chemokine axes, extracellular traps, and efferocytosis, mediate context-specific reprogramming of effector states, with extracellular vesicle cargo and trap degradation products emerging as diagnostic and therapeutic targets. Advances in nanomedicine now enable phase-specific manipulation of this myeloid crosstalk, attenuating pathogenic inflammation in the early phase and restoring antimicrobial competence during immunosuppression. Dissecting the spatiotemporal, metabolic, and molecular logic of neutrophil-macrophage communication offers a framework for precision immunomodulation in sepsis, with potential to recalibrate the immune landscape toward controlled inflammation and durable resolution.

Natural killer (NK) cells are the first line of defense against viral infections and tumors. Their cytotoxic activity relies on the formation of an immune synapse (IS) with target cells. The lymphocyte function-associated antigen (LFA)-1 plays a central role in NK cell cytotoxicity by modulating NK-IS assembly and maturation. LFA-1 organization at the IS involves a Golgi-dependent mechanism that has not been fully elucidated. CLIP-associating proteins (CLASP) 1/2 are microtubule plus-tip interacting proteins that control the dynamics of Golgi-derived microtubules (GDMTs). In the present study, we found that CLASP1/2 depletion impaired LFA-1 organization at the IS and inhibited the polarization of the centrosome and the lytic granules toward the target cell, thereby compromising NK cytotoxic function. Our results also revealed the role of the Golgi apparatus as a microtubule-organizing center (MTOC) in these cells. Furthermore, we found that, similar to what was described in other cell types, NK cells require CLASP1/2 and AKAP350 for efficient nucleation of microtubules at the Golgi. Overall, this study uncovers the role of CLASP1/2 in the maturation of the lytic IS in NK cells and presents evidence supporting the contribution of GDMTs in this process.

Low-density granulocytes (LDGs) are a population of predominantly neutrophils that sit within the peripheral blood mononuclear cell layer following density centrifugation. Their presence in various inflammatory conditions raises the question of their role in disease pathogenesis. LDGs may be a heterogeneous population identified to contain cells with variously activated, mature, and immature phenotypes depending on the context. There is a lack of specific marker for these cells, leading to variation in how their surface phenotype is characterized. Differences in the phenotype of LDGs from healthy individuals and during pregnancy compared with those seen in the disease state suggest that distinct subsets of LDGs emerge during inflammatory disease. Subsets of LDGs may contribute to the pathogenesis of disease through their proinflammatory functions, longevity in peripheral blood, and retention within microvascular tissue, leading to damage of endothelial cells. LDGs may also enhance the adaptive immune response through their interactions with T cells. Further research to define LDG surface phenotype and the expression and functions of distinct subsets in inflammatory diseases may identify these cells as potential therapeutic targets.

α(1,3)-exofucosylation is an enzymatic process whereby the monosaccharide L-fucose is added in α(1,3)-linkage onto a pertinent acceptor glycan displayed by a cell membrane glycoprotein or glycolipid. One pertinent acceptor glycan is the terminal trisaccharide unit known as a "sialylated type 2 lactosamine". In this case, α(1,3)-exofucosylation creates the glycan motif sialylated Lewis X (sLeX, CD15 s), the canonical E-selectin binding determinant. At sites of tissue inflammation, endothelial E-selectin enables sLeX-laden blood-borne cells to migrate to, and then extravasate at, diseased sites. Thus, α(1,3)-exofucosylation facilitates T cell tissue infiltration. Considerable data demonstrate the capacity of regulatory T cells (Tregs) to suppress pro-inflammatory processes in the central nervous system. In this review, we describe how α(1,3)-exofucosylation of antigen-specific Tregs can be harnessed to optimize neuroprotection and neurorestoration for both inflammatory and neurodegenerative diseases.

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, affects millions worldwide, with a high prevalence in Latin America, representing a significant public health burden. The transition from the asymptomatic acute phase to the chronic stage, where about 30% of individuals develop cardiomyopathy, poses a scientific challenge. This study explored the role of Toll-like receptor 2 (TLR2) and interleukin-1β (IL-1β) in the pathogenesis of systolic dysfunction in chronic Chagas cardiomyopathy (CCC). Through flow cytometry analysis of CD14 + HLA-DR+ cells, after trypomastigote infection assays, we observed higher TLR2 expression and activation in patients with preserved systolic function and systolic dysfunction (SD) compared to those without cardiac abnormalities. Notably, patients with SD exhibited higher percentages of NF-κβ + IL-1β+ cells and of mean fluorescence intensity of IL-1β in CD14 + HLA-DR + TLR2 + NF-κβ+ cells. A significant negative correlation was observed between left ventricular ejection fraction and IL-1β expression. These findings suggest that higher TLR2-mediated IL-1β production, likely through NF-κβ activation, plays a critical role in the development of systolic dysfunction in CCC. This study provides clinical evidence supporting the TLR2-NF-κβ-IL-1β axis as a potential therapeutic target for mitigating cardiac damage in CCC, considering the progression to chronic and symptomatic cases.

Mycoplasma pneumoniae (Mp) is a frequent cause of pediatric pneumonia, largely due to the challenges in early detection and the tendency to underestimate the severity of infections. Emerging evidence suggests that ATP-binding cassette transporter G1 (ABCG1) plays a critical role in preventing lung inflammation. Our study investigates the connection between ABCG1 and Mycoplasma pneumoniae pneumonia (MPP) and explores the mechanisms involved, with the goal of providing a theoretical basis for the clinical diagnosis of MPP in children. The influence of Mp infection on ABCG1 expression levels in murine neutrophil cell line (MNHC) was examined, followed by a combination of shRNA interference, quantitative reverse transcription polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay to explore the role of ABCG1 in Mp-induced pyroptosis of neutrophils. Additionally, we explored the clinical correlation between ABCG1 expression and NLRP3 inflammasome activation in children with MPP. Mp infection led to decreased ABCG1 expression in murine neutrophils, which in turn boosted NLRP3 levels. The elevated NLRP3 activated the Caspase-1/GSDMD pathway, driving neutrophil pyroptosis and the release of IL-1β and IL-18. These events aggravated the inflammatory response induced by Mp infection. Our clinical data also indicated a significant negative correlation between the mRNA expression of ABCG1 and NLRP3 in peripheral blood and neutrophils of children with MPP. ABCG1 can mitigate pediatric MPP by regulating the NLRP3/Caspase-1 pathway to inhibit neutrophil pyroptosis. This mechanism indicates that ABCG1 could be a valuable biomarker for pediatric MPP, with significant implications for clinical management.