IL-4 standard: a core cytokine in bone marrow hematopoiesis regulation and tumor immune suppression

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This article focuses on the molecular characteristics and biological functions of interleukin-4 (IL-4), systematically elaborating the molecular mechanisms by which it drives the generation of immunosuppressive myeloid cells through bone marrow hematopoiesis regulation in the tumor microenvironment, analyzing the pathological role of IL-4 as a major driver of tumor-infiltrating monocyte-derived macrophages, and exploring the potential clinical value of targeting the IL-4 signaling pathway in tumor immunotherapy.

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IL-4 Standard: A Core Cytokine in Bone Marrow Hematopoietic Regulation and Tumor Immunosuppression

Brief Introduction: This article focuses on the molecular characteristics and biological functions of interleukin-4 (IL-4), systematically elaborating on the molecular mechanism by which it drives the generation of immunosuppressive myeloid cells through bone marrow hematopoietic regulation within the tumor microenvironment, analyzing the pathological role of IL-4 as the major driver of tumor-infiltrating monocyte-derived macrophages, and exploring the potential clinical value of targeting the IL-4 signaling pathway in tumor immunotherapy.

I. Immune cell remodeling during tumorigenesis.

During tumorigenesis, bone marrow progenitor populations, immunosuppressive immature monocytes, and neutrophils among myeloid cells are mobilized into the bloodstream; among lymphoid cells, the frequency of CD4+ Tregs and regulatory B cells increases systemically, and prior to infiltrating the tumor, Treg cells undergo specific clonal expansion in the periphery; the frequency of dendritic cells and CD8+ CD4+ T cells and the diversity of the T cell receptor repertoire decrease. Mouse models have also observed the accumulation of immature neutrophils, monocytes, and dendritic cells, along with decreased abundance of dendritic cell and T cell populations. Draining lymph nodes, which have the most direct communication with the tumor, are characterized by increased frequencies of monocytes and dendritic cells and decreased CD8+ T cells. Therefore, the accumulation of immature myeloid cells is one of the most important strategies for tumor immune evasion.

II. IL-4 as a key driver of tumor immunosuppressive myelopoiesis.

In October 2023, Professor Miriam Merad's team at the Icahn School of Medicine at Mount Sinai in the United States published a paper titled "An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis" in the journal Nature, discovering that IL-4 is the major driver of tumor-infiltrating monocyte-derived macrophages, revealing the mechanism by which bone marrow-derived IL-4 acts on granulocyte-monocyte progenitor cells to drive the generation of immunosuppressive myeloid cells; and determining the role of IL-4 in tumor immunosuppressive myelopoiesis and its potential clinical application value as a combination therapy with immune checkpoint blockade.

The researchers' previous work used single-cell RNA sequencing to map the immune landscape of human and mouse non-small cell lung cancer lesions, defining a novel myeloid cell population——regulatory molecule-enriched mature dendritic cells, which possess immunosuppressive functions. Further in-depth research revealed that the cytokine IL-4 is associated with the regulation of regulatory molecule-enriched mature dendritic cells, and blocking IL-4 significantly reduced lung tumor burden in mice with orthotopic KrasG12DTp53-/- lung adenocarcinoma lesions and B16 melanoma lung metastasis mice. However, mice with specific dendritic cell IL-4 receptor IL-4Ra deficiency, tissue-resident dendritic cell IL-4Ra deficiency, or T cell IL-4Ra deficiency showed no significant differences in tumor burden. Therefore, there must be another immune cell type that can respond to IL-4 to promote tumor development.

III. Functional validation of IL-4 signaling in granulocyte-monocyte progenitor cells.

Based on the above findings, the researchers conducted further research on human and mouse non-small cell lung cancer transcriptomic datasets. Gene set enrichment analysis of differentially expressed genes in lung cancer-infiltrating monocyte-macrophages and tissue-resident monocytes revealed that the IL-4 signaling pathway had the highest enrichment among human monocyte-derived macrophage-specific genes and the second highest enrichment in mice.

Therefore, the researchers crossed Il4ra-floxed mice with Ms4a3-cre mice, in which Cre is highly expressed in bone marrow granulocyte-monocyte progenitor cells and can induce gene deletion in all downstream cell lineages while preserving tissue-resident monocytes. Results from the animal model showed that compared with control wild-type mice, Il4raΔMs4a3 mice exhibited an 85% reduction in tumor burden, suggesting that IL-4 signaling in granulocyte-monocytes is critical for tumor suppression. Meanwhile, lung monocyte-derived macrophages and circulating monocytes were significantly reduced in tumor-bearing Il4raΔMs4a3 mice. Therefore, the researchers subsequently focused their research on the monocyte-monocyte-derived macrophage lineage.

IV. Reprogramming effects of IL-4Ra deficiency on the tumor microenvironment.

Single-cell RNA sequencing of bone marrow cells from tumor-bearing mice of both genotypes captured all expected immune cell populations, including two monocyte-derived macrophage populations with low and high Trem2 expression, and each monocyte-derived macrophage cluster showed significant differences in Il4raΔMs4a3 mouse cells. Immunohistochemistry results also showed significant changes in immune cells in lung tumors of Il4raΔMs4a3 mice, indicating that in all granulocyte-monocyte progenitor cell-derived lineages, Il4ra deletion enhanced the immunogenicity of monocytes and monocyte-derived macrophages and reprogrammed the lung tumor microenvironment to an inflammatory anti-tumor state.

However, after crossing Il4ra-floxed with Cx3cr1-cre or S100a8-cre mice, no reduction in lung tumor burden was observed, as these two genes are expressed in more mature myeloid cells downstream of granulocyte-monocyte progenitor cells and are strongly biased toward monocyte and neutrophil lineages, respectively. Therefore, IL-4Ra deficiency in early bone marrow myeloid progenitor cells drives lung tumor microenvironment reprogramming and reduction of lung tumor burden, but deficiency in mature monocyte-derived macrophages and neutrophils had no effect.

V. Cellular source and working model of the bone marrow IL-4 signaling axis.

Further research found that IL-4Ra signaling participates in regulating the transcriptional expression of bone marrow progenitor cells in tumor-bearing mice, and these phenotypes can be reproduced by exposing bone marrow to IL-4 in vivo. The researchers also found that basophils are the main source of IL-4 in the bone marrow, rather than lung cancer tissue. Based on this, the authors proposed a model: the tumor microenvironment produces soluble components that reach the bone marrow through peripheral circulation and act on type 2 granulocytes in the bone marrow; basophils produce IL-4, which then regulates the differentiation of immunosuppressive myeloid cells and tumor progression through its receptor IL4Ra. This model reveals a long-range signal transmission mechanism from the tumor microenvironment to bone marrow hematopoietic regulation.

VI. Conclusion.

In IL-4-related basic research and drug development, high-quality recombinant IL-4 standards are core tools for dissecting its signal transduction mechanisms and evaluating its biological functions. In response to the needs of IL-4 functional research and detection method development, Univ provides IL-4 Protein, Mouse. This product is suitable for applications including mouse IL-4/IL-4Ra signaling pathway mechanism research, bone marrow hematopoietic regulation research, tumor immune microenvironment analysis, and the establishment and validation of IL-4 immunoassays.

As a key driver of tumor immunosuppressive myelopoiesis, IL-4, by virtue of its unique mechanism of regulating immunosuppressive myeloid cell differentiation through IL-4Ra signaling in bone marrow granulocyte-monocyte progenitor cells, has become an important molecular node connecting the tumor microenvironment and bone marrow hematopoietic regulation. From soluble components of the tumor microenvironment reaching the bone marrow through peripheral circulation, to basophils producing IL-4, to IL-4Ra signaling driving the generation of immunosuppressive myeloid cells and tumor progression, this complete signaling axis provides a new target direction for tumor immunotherapy. IL-4 Protein, Mouse provides reliable tool support for the in-depth analysis of the IL-4 signaling network and the development of targeted therapeutic strategies, and will continue to drive innovative exploration in the field of tumor immunology.

This article is reviewed and published by the technical expert team of UA

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

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