Intestinal Epithelium–Derived IL-34 Reprograms Macrophages to Mitigate Gastrointestinal Tract Graft-Versus-Host Disease

Rheumatology and Immunology Immunology Medicine Basic Medical Sciences Gastroenterology Hematology Life Sciences Cell Biology
Graft-versus-host disease Macrophages IL-34 Intestinal epithelium Immunomodulation

Academic Report on the Role of Intestinal Epithelium-Derived IL-34 in Alleviating Graft-versus-Host Disease

1. Academic Background

Graft-versus-Host Disease (GVHD) is a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), and gastrointestinal (GI) GVHD is the primary determinant of morbidity and mortality during the acute phase of the disease. The pathophysiology of GVHD involves complex interactions within the immune system, including both adaptive and innate immunity. Although regulatory T cells (Tregs) play a primary role in suppressing GVHD-induced inflammation, identifying and utilizing other pathways to promote immune tolerance remains a critical goal in the field.
In recent years, researchers have found that the role of macrophages in GVHD remains unclear, particularly in the gastrointestinal tract. The survival and proliferation of macrophages depend on ligand interactions with the Colony-Stimulating Factor 1 Receptor (CSF-1R). Interleukin-34 (IL-34), another ligand of CSF-1R, was initially thought to be primarily expressed in the skin and brain, but subsequent studies have revealed its widespread presence in various tissues and its important role in immune regulation. However, the specific mechanisms of IL-34 in GVHD, particularly how it mitigates gastrointestinal GVHD inflammation by regulating macrophages, remain unclear.
The purpose of this study is to explore the role of IL-34 in gastrointestinal GVHD, especially its specific mechanisms in regulating macrophage polarization and alleviating inflammation, providing new potential therapeutic targets for GVHD.

2. Source of the Paper

This research was conducted by Aditya Rayasam, Alison Moe, and other researchers from multiple institutions, including the Medical College of Wisconsin. The study was published in the journal Science Translational Medicine on February 12, 2025.

3. Research Design

3.1 Research Objectives

The core objective of this study is to elucidate the mechanisms of IL-34 in gastrointestinal GVHD, particularly how it alleviates inflammatory responses by regulating macrophage polarization. Through a series of experiments, the research team validated the expression of IL-34 in intestinal epithelial cells and its regulatory effects on macrophages and T cells, while also exploring its potential clinical applications.

3.2 Methods and Procedures

3.2.1 Animal Models and Experimental Groups

The study used a major histocompatibility complex (MHC)-mismatched mouse model (B10.Br → C57BL/6) to simulate GVHD. The experimental groups included a control group receiving bone marrow transplantation (BM) and a GVHD group receiving spleen cell transplantation. Additionally, IL-34 knockout (IL-34−/−) mouse models were constructed to study the role of IL-34 in GVHD.

3.2.2 Phenotypic and Transcriptomic Analysis of Macrophages

Using flow cytometry and single-cell RNA sequencing (scRNA-seq), the research team analyzed the phenotypic and transcriptomic characteristics of macrophages in the colons of GVHD mice. The results showed significant phenotypic and transcriptional heterogeneity in macrophages from GVHD mice, including pro-inflammatory (Ly6C+) and anti-inflammatory (Ly6C−) subsets.

3.2.3 Functional Validation of IL-34

To validate the role of IL-34 in GVHD, the research team treated GVHD mice with recombinant IL-34 and assessed their survival rates, inflammatory responses, and histopathological changes. Additionally, bone marrow chimeric mouse models were constructed to study the role of IL-34 in hematopoietic and non-hematopoietic systems.

3.2.4 Human Sample Validation

The study also analyzed colon biopsy samples from human allogeneic hematopoietic stem cell transplantation (Allogeneic HSCT) patients to validate the expression of IL-34 in intestinal epithelial cells and its correlation with pathological changes in GVHD.

3.3 Key Results

3.3.1 Protective Role of IL-34 in GVHD

The study found that the absence of IL-34 significantly exacerbated mortality, intestinal epithelial cell death, and barrier dysfunction in GVHD mice. Conversely, administration of recombinant IL-34 significantly reduced GVHD mortality and inflammation, indicating a protective role of IL-34 in GVHD.

3.3.2 IL-34 Regulates Macrophage Polarization

The absence of IL-34 led to the polarization of macrophages toward a pro-inflammatory phenotype and increased the accumulation of CD4+ GM-CSF+ T cells in the colon. Administration of recombinant IL-34 significantly reduced the number of these pro-inflammatory cells.

3.3.3 ApoE Expression Dependent on IL-34

Mechanistic studies revealed that the protective effects of IL-34 depended on the expression of Apolipoprotein E (ApoE) in macrophages. ApoE was significantly upregulated in the colons of GVHD mice and was closely associated with its anti-inflammatory effects.

3.3.4 Human Sample Validation Results

In colon biopsies from human GVHD patients, IL-34 was expressed in intestinal epithelial cells, while ApoE was expressed in lamina propria macrophages, confirming similar cellular localization of IL-34 and ApoE in human GVHD.

3.4 Conclusions and Significance

This study demonstrates that intestinal epithelium-derived IL-34 alleviates inflammation in gastrointestinal GVHD by regulating macrophage polarization. The protective effects of IL-34 depend on ApoE expression in macrophages, providing new potential therapeutic targets for GVHD.

4. Research Highlights

  • Key Finding: IL-34 exerts protective effects in GVHD by regulating macrophage polarization, a mechanism that depends on ApoE expression.
  • Innovative Methods: Single-cell RNA sequencing and bone marrow chimeric models were used to elucidate the specific mechanisms of IL-34 in GVHD.
  • Clinical Application: Recombinant IL-34 may be an effective strategy for treating GVHD, particularly in alleviating gastrointestinal inflammation.

5. Other Valuable Information

The study also found that IL-34 expression correlates with the extent of tissue damage in GVHD patients, providing a new biomarker for clinical diagnosis and treatment. Additionally, the IL-34-dependent ApoE mechanism proposed by the research team offers a new direction for future studies on the role of macrophages in GVHD.