Journal of Leukocyte Biology最新文献

Arginine metabolism supports metabolic reprogramming in trained immunity. 精氨酸代谢支持训练免疫的代谢重编程。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-04 DOI: 10.1093/jleuko/qiaf080

Laura M Merlo Pich, Athanasios Ziogas, Anaisa V Ferreira, Nicholas Sumpter, Andrei Sarlea, Sarantos Kostidis, Leo A B Joosten, Mihai G Netea

{"title":"Arginine metabolism supports metabolic reprogramming in trained immunity.","authors":"Laura M Merlo Pich, Athanasios Ziogas, Anaisa V Ferreira, Nicholas Sumpter, Andrei Sarlea, Sarantos Kostidis, Leo A B Joosten, Mihai G Netea","doi":"10.1093/jleuko/qiaf080","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf080","url":null,"abstract":"Trained immunity, also termed innate immune memory, is supported by metabolic rewiring of innate immune cells, altering their bioenergetic profile and ultimately their functions. While amino acids such as arginine are known to possess immunomodulatory properties, their role in trained immunity remains largely unexplored. Primary human monocytes were trained with β-glucan in a medium enriched with or deprived of arginine or supplemented with an arginase inhibitor. After a resting period, trained cells were restimulated with LPS. Arginine deprivation or arginase inhibition during β-glucan-training impaired the amplification of IL-6 and TNF cytokine response to LPS, while they did not affect the cells' phagocytotic capacity. Arginine deprivation also significantly reduced the oxygen consumption rate of trained cells, without affecting glycolysis. Genetic studies revealed polymorphisms near genes coding for arginine-metabolizing enzymes modulated induction of trained immunity, highlighting the role of arginine-derived metabolites in trained immunity. These findings demonstrate that arginine and its metabolites are involved in the induction of trained immunity. Understanding metabolic mechanisms involved in trained immunity could provide insights into new therapeutic strategies for harnessing arginine deprivation to modulate inflammatory disorders.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interferon regulatory factor 8 induces intrinsic functional changes in mature neutrophils. 干扰素调节因子8诱导成熟中性粒细胞内在功能改变。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-06-03 DOI: 10.1093/jleuko/qiaf078

Laura Polmann, Janna Carina Grimm, Johannes Roth, Katarzyna Barczyk-Kahlert

{"title":"Interferon regulatory factor 8 induces intrinsic functional changes in mature neutrophils.","authors":"Laura Polmann, Janna Carina Grimm, Johannes Roth, Katarzyna Barczyk-Kahlert","doi":"10.1093/jleuko/qiaf078","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf078","url":null,"abstract":"Neutrophils are the first line of host defense. Neutrophils target invading pathogens by phagocytosis, generation of reactive oxygen species (ROS), neutrophil extracellular trap formation (NETosis) and cytokine production. Interferon regulatory factor 8 (IRF8) plays a central role in the regulation of myeloid cells fate, promoting monocyte and dendritic cell development while inhibiting neutrophil production. The global IRF8 deficiency leads to an accumulation of immature myeloid cells, mostly neutrophils, while IRF8 deficiency restricted to myeloid cells has no effect on myeloid cell differentiation. However, the role of IRF8 in regulating neutrophil function remains to be fully elucidated, especially due to the fact that IRF8 is not expressed in mature neutrophils. This study aims to investigate the impact of IRF8 on effector functions of neutrophils. The absence of IRF8 resulted in diminished response of neutrophils to inflammatory challenge by lipopolysaccharide (LPS), as evidenced by reduced expression of inflammatory cytokines. This effect was intrinsic to IRF8-/- neutrophils and not driven by extrinsic factors, as assessed comparing bone marrow-derived and ER-HoxB8-derived IRF8-/- neutrophils and was accompanied by reduced p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) activation. It is noteworthy that not all effector functions were affected by IRF8 deficiency. The mechanisms of pathogen elimination, such as phagocytosis and ROS production, were impaired in IRF8-/- neutrophils, whereas processes like NETosis remained entirely intact. In conclusion, our findings suggest that IRF8 shapes neutrophil response to LPS and modulates neutrophil function, and this process is independent of external factors.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A comprehensive phenome wide analysis of the role of neutrophils in health and disease. 中性粒细胞在健康和疾病中的作用的综合表型分析。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-05-28 DOI: 10.1093/jleuko/qiaf076

Katy Fleming, Naomi Cornish, Emma E Vincent, Andrew D Mumford, Borko Amulic, Kate Burley

引用次数: 0

TFEB-Mediated Pro-inflammatory Response in Murine Macrophages Induced by Acute Alpha7 Nicotinic Receptor Activation. 急性α - 7烟碱受体激活诱导小鼠巨噬细胞tfeb介导的促炎反应

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-05-28 DOI: 10.1093/jleuko/qiaf077

Havisha H Honwad, Mehran Najibi, Savior Watts, Accalia M Fu, Balazs Koscso, Milena Bogunovic, Javier E Irazoqui

{"title":"TFEB-Mediated Pro-inflammatory Response in Murine Macrophages Induced by Acute Alpha7 Nicotinic Receptor Activation.","authors":"Havisha H Honwad, Mehran Najibi, Savior Watts, Accalia M Fu, Balazs Koscso, Milena Bogunovic, Javier E Irazoqui","doi":"10.1093/jleuko/qiaf077","DOIUrl":"10.1093/jleuko/qiaf077","url":null,"abstract":"Transcription factors TFEB and TFE3 are crucial for regulating autophagy, lysosomal biogenesis, and lipid metabolism, and have significant roles in macrophage function and innate immunity. The alpha7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated Ca2+ channel known for its therapeutic potential in neurological and inflammatory disorders, has been implicated in modulating immune responses by modulating macrophage function. Stimulation of α7nAChR with chemical agonists has been claimed to activate TFEB in pancreatic acinar cells and neurons. However, the impact of α7nAChR activation on TFEB and TFE3 in macrophages remained unknown, posing an important question due to the potential implications for inflammation regulation. This study investigates the effects of acute α7nAChR activation on TFEB-mediated responses in murine macrophages using the specific agonist PNU-282987. We demonstrate that α7nAChR stimulation triggers TFEB nuclear translocation and lysosomal expansion. Surprisingly, PNU-282987 induces a broad pro-inflammatory gene signature without concomitant cytokine secretion, suggesting an uncoupling of gene expression from cytokine release. Mechanistically, TFEB activation requires the lysosomal Ca2+ exporter MCOLN1 and the Ca2+-dependent phosphatase PPP3/calcineurin. Additionally, PNU-282987 elevates reactive oxygen species (ROS) levels, and ROS are involved in TFEB activation by PNU-282987. Notably, even with α7nAChR deletion, compensatory ROS-mediated TFEB activation persists, suggesting the involvement of additional mechanisms of action for PNU-282987. Our findings reveal a novel α7nAChR-TFEB signaling axis in macrophages, offer new insights into the cholinergic regulation of immune responses, establish a baseline for comparison with disease states, and identify potential therapeutic targets for modulating inflammation.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From Killers to Hoplites: Neutrophils in Skin Barrier Defense. 从杀手到重装步兵：皮肤屏障防御中的中性粒细胞。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-05-27 DOI: 10.1093/jleuko/qiaf074

Austin Lowery, Yanfang Peipei Zhu, Catherine C Hedrick

引用次数: 0

Macrophage Polarization, Inflammatory Monocytes, and Impaired MDSCs are Associated with Murine and Human Immune Aplastic Anemia. 巨噬细胞极化、炎性单核细胞和MDSCs受损与小鼠和人类免疫再生障碍性贫血有关。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-05-24 DOI: 10.1093/jleuko/qiaf073

Joshua Glass, Xingmin Feng, Jichun Chen, Jibran Durrani, Zhijie Wu, Shouguo Gao, Ruba Shalhoub, Liangliang Wu, Neal S Young

{"title":"Macrophage Polarization, Inflammatory Monocytes, and Impaired MDSCs are Associated with Murine and Human Immune Aplastic Anemia.","authors":"Joshua Glass, Xingmin Feng, Jichun Chen, Jibran Durrani, Zhijie Wu, Shouguo Gao, Ruba Shalhoub, Liangliang Wu, Neal S Young","doi":"10.1093/jleuko/qiaf073","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf073","url":null,"abstract":"Immune-mediated bone marrow failure (BMF) entails a complex immune landscape. Myeloid cells, including monocytes, macrophages, and myeloid-derived suppressor cells (MDSCs), are involved in the development and progression of immune aplastic anemia (AA). We used a murine model of BMF to explore the effects of CSF-1R inhibition on immune pathophysiology. Hematopoiesis, immune cell populations, and gene expression were assessed by flow cytometry, cytokine analysis, and single-cell RNA sequencing. CSF-1R inhibition with the small molecule PLX3397 intensified BMF in CByB6F1 mice, enhancing inflammation and macrophage polarization toward the pro-inflammatory M1 phenotype. This was accompanied by increased leukocyte apoptosis, a reduction in CD11b+ myeloid cells, and worsened animal survival. In contrast, the JAK-inhibitor baricitinib attenuated BMF, promoting M2 macrophage polarization, and decreasing CD8+ T cell infiltration of bone marrow. Single-cell RNA analysis revealed upregulation of M1 signature genes in both murine BMF and also AA human samples. In patients with severe AA, there was a shift towards an M1-like monocyte phenotype, correlating with increased inflammatory cytokine expression and altered MDSC populations. These findings highlight the role of myeloid-derived cells in BMF and suggest that M1 macrophages, with defective MDSC function, contribute to disease pathogenesis and progression. Targeting macrophage polarization or MDSCs offers alternative therapeutic strategies in immune-mediated BMF.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microenvironmental Conditions and Serum Availability Alter Primary Human Macrophage NF-κB Inflammatory Response and Function. 微环境条件和血清可用性改变原代人巨噬细胞NF-κB炎症反应和功能。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-05-22 DOI: 10.1093/jleuko/qiaf071

Breana Channer, Marzieh Daniali, Lexi Sheldon, Katy Emanuel, Yash Agarwal, Taylor Kist, Brian J Murphy, Meng Niu, Will Dampier, Howard Fox, Peter J Gaskill

{"title":"Microenvironmental Conditions and Serum Availability Alter Primary Human Macrophage NF-κB Inflammatory Response and Function.","authors":"Breana Channer, Marzieh Daniali, Lexi Sheldon, Katy Emanuel, Yash Agarwal, Taylor Kist, Brian J Murphy, Meng Niu, Will Dampier, Howard Fox, Peter J Gaskill","doi":"10.1093/jleuko/qiaf071","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf071","url":null,"abstract":"Macrophages are central to innate immunity and are routinely used in vitro to examine molecular mechanisms contributing to innate immune signaling. However, there is a lack of consensus within the field for optimal in vitro culturing methods, and it is not well understood whether differences in culture conditions produce incongruent outcomes. Here, we compared the effects of commonly used culture medium compositions on TLR4-mediated pro-inflammatory activity in primary human monocyte-derived macrophages (hMDM) isolated from healthy blood donors. hMDM were cultured in fetal bovine serum (FBS)-containing or FBS-free conditions in either DMEM, RPMI, or in Macrophage-Serum Free Medium (M-SFM). LPS-mediated immune response was measured through NF-κB activation and cytokine and chemokine secretion, which were muted in M-SFM cultures compared to DMEM and RPMI cultures. FBS supplementation increased total cytokine secretion in response to LPS but also showed higher baseline secretion, suggesting a pro-inflammatory phenotype. Moreover, M-SFM cultures exhibited less phagocytosis compared to DMEM and RPMI cultures. Morphologic analysis of unstimulated hMDM revealed the highest cell area and length-to-width ratio in M-SFM compared to DMEM or RPMI cultures. FBS-free and M-SFM conditions produced distinct transcriptional profiles compared to media supplemented with FBS, most notably in cell cycle pathways and lipid homeostasis, respectively. Overall, DMEM and RPMI produce comparable morphologic and functional results, albeit with some small differences, while M-SFM produces a muted inflammatory response in macrophages. These data demonstrate that in vitro microenvironment drives differential inflammatory outcomes in human macrophages and is a critical component of experimental design in this cell type.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AML1-ETO and CCND2 overexpression- cooperate to drive acute myeloid leukemia initiation and progression. AML1-ETO和CCND2过表达共同驱动急性髓系白血病的发生和发展。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-05-22 DOI: 10.1093/jleuko/qiaf072

Junli Mou, Qianqian Huang, Xiaoyu Liu, Wenbing Liu, Yu Liu, Yihan Mei, Runxia Gu, Yingxi Xu, Kejing Tang, Zheng Tian, Haiyan Xing, Qing Rao, Min Wang, Shaowei Qiu, Jianxiang Wang

{"title":"AML1-ETO and CCND2 overexpression- cooperate to drive acute myeloid leukemia initiation and progression.","authors":"Junli Mou, Qianqian Huang, Xiaoyu Liu, Wenbing Liu, Yu Liu, Yihan Mei, Runxia Gu, Yingxi Xu, Kejing Tang, Zheng Tian, Haiyan Xing, Qing Rao, Min Wang, Shaowei Qiu, Jianxiang Wang","doi":"10.1093/jleuko/qiaf072","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf072","url":null,"abstract":"Increasing numbers of clinical cohorts have detected CCND2 mutations in acute myeloid leukemia (AML), especially in the subtype of AML with t(8;21) translocation. As known, this AML subtype is characterized by the formation of AML1-ETO fusion gene. However, AML1-ETO fusion gene alone is not sufficient to drive leukemia development, additional mutations are required for leukemogenesis. In this study, we aim to investigate whether mutated CCND2 can cooperate with AML1-ETO fusion gene to drive leukemia initiation and progression. In our previous study, the conditional AML1-ETO knock-in mouse model (AML1/ETO mouse), which represented a pre-leukemia stage as myeloproliferative neoplasm phenotype, was established. To confirm whether the AML1-ETO and CCND2 mutation can cooperate to drive leukemia, the mice transduction and transplantation model harboring both AML1-ETO and CCND2 gene (both wildtype and mutant) were established. Upon the assessment of the phenotype, biological features and survival of the mice, only the mice overexpressing the AML1-ETO and CCND2 simultaneously were eventually progressed to leukemia. Besides, compared to mice overexpressing AML-ETO gene alone, mTOR and cell cycle-related pathways were significantly enriched in mice harboring both AML1-ETO and CCND2. And the selective mTOR inhibitor, Everolimus, can reduce the leukemia burden and prolong the survival of this group of mice. In conclusion, it was confirmed that introduction of the CCND2 gene into the AML/ETO pre-leukemia mice could trigger the development of leukemia. It was also confirmed that CCND2 overexpression resulted in the upregulation of the mTOR pathway and inhibiting the pathway might be a therapeutic strategy for this subtype of leukemia.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nervonic acid mitigates IMQ-triggered psoriasis in mice via inhibiting Th17/γδT17 cell invasion and modulating the gut microbiota. 神经酸通过抑制Th17/γδT17细胞侵袭和调节肠道微生物群减轻imq引发的小鼠牛皮癣。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-05-21 DOI: 10.1093/jleuko/qiaf070

Zishan Yang, Xiaorong Geng, Shenglan Zhang, Junjie Gao, Fengxiang Ji, Yixuan Han, Zhihao Cui, Xia Wang, Sheng Guo, Dong Yan, Tiesuo Zhao, Feng Ren, Xueshi Li, Jie Dong, Zhongwei Tian, Zhinan Yin, Xiangfeng Song

{"title":"Nervonic acid mitigates IMQ-triggered psoriasis in mice via inhibiting Th17/γδT17 cell invasion and modulating the gut microbiota.","authors":"Zishan Yang, Xiaorong Geng, Shenglan Zhang, Junjie Gao, Fengxiang Ji, Yixuan Han, Zhihao Cui, Xia Wang, Sheng Guo, Dong Yan, Tiesuo Zhao, Feng Ren, Xueshi Li, Jie Dong, Zhongwei Tian, Zhinan Yin, Xiangfeng Song","doi":"10.1093/jleuko/qiaf070","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf070","url":null,"abstract":"Psoriasis is a persistent immune-mediated inflammatory dermatosis. The treatment of psoriasis now features natural medicine as an effective new alternative because of its notable effectiveness and few side effects. Nervonic acid (NA), a long-chain fatty acid mostly sourced from the seed oils of some wild plants, exhibits significant antidepressant and anti-inflammatory properties. Nonetheless, the pathogenic effects and mechanism of NA in the pathogenesis of psoriasis are unreported. This work demonstrated that NA markedly mitigated IMQ-triggered psoriasis-like skin inflammation and reduced the mRNA expression levels of chemokines (Cxcl1 and Ccl20) and inflammatory factors (S100a8, S100a9, IL-17, and IL-6) both in vitro and in vivo. Mechanistically, NA blocked the IL-17/IMQ-induced NF-κB and p38MAPK signaling pathways in keratinocytes or tissue lesions, downregulated Ccl20 production, and therefore disrupted positive inflammatory feedback by diminishing Th17 or γδT17 cell infiltration. Furthermore, 16s rRNA sequencing demonstrated that NA therapy significantly elevated the relative abundance of Bacteroidota, but the outcome for Mucispirillum was contrary within the gut microbiota. These bacteria are linked to the onset of psoriasis and inflammation, perhaps contributing to the alleviation of IMQ-induced lesions in mice. In conclusion, NA may alleviate dermatitis in psoriatic mice by inhibiting Th17/γδT17 cell invasion and modulating the gut microbiota. Consequently, NA stands as a highly promising choice for psoriasis treatment.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TIPE regulates TGFB2 expression and induces extracellular M2 polarization in CRC. TIPE调节CRC中TGFB2的表达，诱导细胞外M2极化。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-05-20 DOI: 10.1093/jleuko/qiaf066

Qiang Zhu, Shiying Zhang, Changxiu Yan, Zeyang Lin, Shuaishuai Zhang, Haoyang Li, Yuhan Ye, Zhongchen Liu, Guohong Zhuang, Kun Zhang

{"title":"TIPE regulates TGFB2 expression and induces extracellular M2 polarization in CRC.","authors":"Qiang Zhu, Shiying Zhang, Changxiu Yan, Zeyang Lin, Shuaishuai Zhang, Haoyang Li, Yuhan Ye, Zhongchen Liu, Guohong Zhuang, Kun Zhang","doi":"10.1093/jleuko/qiaf066","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf066","url":null,"abstract":"The immunosuppressive tumor microenvironment (TME) is a critical determinant of therapeutic resistance in colorectal cancer (CRC). The TME encompasses diverse cellular and stromal elements, including tumor cells, immune cells, extracellular matrix (ECM), and lymphatic vessels. Among these components, tumor-associated macrophages (TAMs) predominate both quantitatively and functionally, with M2-polarized macrophages being the principal subset responsible for immunosuppression. Identifying genes that promote M2 polarization from CRC would provide a more targeted approach to addressing this issue at its root. In this study, we demonstrate that TIPE derived from CRC indirectly stimulates extracellular M2 polarization. Mechanistically, TIPE activates the P38 MAPK signaling pathway, leading to increased expression and secretion of TGFB2, which subsequently acts on extracellular macrophages to induce M2 polarization. Moreover, M2 macrophages polarized by CRC-derived factors exert a feedback loop that enhances CRC proliferation, migration, and invasion, with the effect intensifying as TIPE expression in CRC increases. Animal experiments have also revealed that TGFB2 induced by TIPE can disseminate systemically via the bloodstream, influencing not only peritumoral macrophages but also inducing M2 polarization in macrophages in distant organs. Collectively, our findings indicate that TIPE from CRC can indirectly polarize extracellular macrophages to an M2 phenotype, thereby amplifying the malignant behavior of CRC.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0