IL-10 Sensing by Lung Interstitial Macrophages Prevents Bacterial Dysbiosis-Driven Pulmonary Inflammation and Maintains Immune Homeostasis

Rheumatology and Immunology Microbiology Cell Biology Life Sciences Respiratory System Medicine Immunology
IL-10 Lung Interstitial Macrophages Bacterial Dysbiosis Pulmonary Inflammation Immune Homeostasis Chronic Inflammation Microbiota

1. Research Background

The pathogenesis of chronic lung inflammation and pulmonary fibrosis remains unclear, particularly regarding the interaction between pulmonary commensal microbiota and the immune system. While interleukin-10 (IL-10), a key anti-inflammatory cytokine, has been extensively studied in gut homeostasis, its role in pulmonary immune regulation remains poorly understood. This study focuses on how IL-10 signaling deficiency triggers bacterial dysbiosis-driven inflammation via lung interstitial macrophages (IMs) and explores its synergistic mechanisms with Th17 cells and monocytes.

2. Source of the Study

This research was conducted by Seung Hyon Kim (Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago), Teruyuki Sano (Department of Microbiology and Immunology), and 14 other collaborators. It was published on May 13, 2025, in the top-tier immunology journal Immunity (Elsevier, DOI:10.1016/j.immuni.2025.04.004).

3. Research Process and Findings

a) Research Workflow

1. Phenotypic Validation and Model Construction

  • Study Subjects:
    • IL-10 knockout mice (IL10–/–) and wild-type (WT) controls at different ages (8/16/30 weeks).
    • Conditional knockout mice: CX3CR1-Cre-mediated IL10ra deletion (cx3cr1δil10ra), targeting IMs and classical monocytes (cMs).
  • Methods:
    • Histopathology (H&E staining, Masson’s trichrome staining) revealed non-specific chronic inflammation (lymphocytic infiltration, peribronchial fibrosis) in IL10–/– mice after 16 weeks.
    • Flow cytometry quantified pulmonary enrichment of neutrophils, cMs, and MHC II+ IMs.
    • Innovative Techniques:
    • Dual-reporter mice (cx3cr1gfp:il10–/–, ly6gtdtomato:il10–/–) enabled spatiotemporal tracking of IMs and neutrophils.
    • Pulse-chase experiments: Tamoxifen-induced IL10ra conditional restoration verified the functional necessity of IMs.

2. Mechanistic Investigation

  • Immune Cell Interactions:
    • CCR2 knockout (il10–/–ccr2–/–) confirmed that cMs differentiation into monocyte-derived IMs (mo-IMs) is essential for inflammation.
    • CD4+ T cell depletion (anti-CD4 antibody) or IL-1R blockade (anti-IL-1R antibody) significantly reduced Th17 cell infiltration, highlighting the IL-1β-Th17 axis as central.
  • Microbiome Analysis:
    • 16S rRNA sequencing identified specific expansion of Delftia acidovorans (Proteobacteria) and Rhodococcus erythropolis (Actinobacteria) in IL10–/– mouse lungs.
    • Germ-free (GF) colonization experiments: Intranasal or oral administration of these bacteria induced lung inflammation in GF il10–/– mice, while segmented filamentous bacteria (SFB) had no effect.

3. Clinical Relevance Validation

  • Human Microbiota Transplantation: RNA-seq showed significant activation of innate immune pathways (e.g., S100A8/9, CSF3R) in the lungs of GF il10–/– mice after human fecal microbiota transplantation (HufMT), whereas gut tissues exhibited tissue-repair pathways.

b) Key Findings

  1. IL-10 Deficiency Disrupts IMs Function:

    • IMs in cx3cr1δil10ra mice lost anti-inflammatory capacity, accompanied by expansion of cMs (Ly6Chi) and mo-IMs (MHC IIhi) (flow cytometry: 3-5-fold increase, p<0.001).
    • Histology revealed basement membrane collagen IV (Col IV) degradation and α-SMA (myofibroblast marker) upregulation (immunoblot: 2.1-fold increase at 30 weeks).

  2. Microbiota-Dependent Inflammation:

    • Antibiotic treatment (ABX) or GF conditions completely blocked inflammation (80% reduction in H&E scores), while mono-colonization with D. acidovorans/R. erythropolis recapitulated pathology (CFU assay: 10^6/g tissue).

  3. Cross-Organ Immune Axis:

    • Gut microbiota activated pulmonary Th17 cells via the gut-lung axis (flow cytometry: 1.8-fold synchronous increase in colonic and pulmonary Th17), but only under IL-10 deficiency.

4. Conclusions and Significance

  1. Scientific Impact:

    • First demonstration that IMs maintain lung commensal homeostasis via IL-10 signaling, filling a gap in IL-10’s extra-intestinal roles.
    • Proposes a “bacteria-IMs-Th17” three-stage inflammation model, offering new mechanistic insights into chronic lung diseases.

  2. Translational Potential:

    • Diagnostic Biomarkers: D. acidovorans/R. erythropolis may serve as microbial markers for IL-10 signaling-deficient lung disorders.
    • Therapeutic Targets: Targeting IL-1R or specific microbiota modulation (e.g., probiotics) could mitigate fibrosis progression.

5. Highlights

  • Methodological Innovation: Integrates conditional knockouts, microbiome sequencing, and cross-organ immune profiling to establish a multi-dimensional mechanistic framework.
  • Clinical Relevance: Human microbiota transplantation model confirms gut microbes can drive lung inflammation, supporting IBD-associated pulmonary complications.
  • Interdisciplinary Integration: Combines immunology, microbiology, and pathology to reveal universal principles of tissue-specific immune regulation.

6. Additional Information

  • Limitations: Unclear virulence factors of D. acidovorans/R. erythropolis; human sample validation requires follow-up studies.
  • Data Availability: Raw sequencing data deposited in NCBI (accession number not specified).