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Background <p>Alveolar type II (ATII) cell transplantation is a promising therapeutic strategy for idiopathic pulmonary fibrosis, although its underlying cellular mechanisms remain incompletely understood. Given that macrophage profibrotic activation is a key driver of fibrosis, we hypothesized that ATII cell therapy exerts antifibrotic effects by reprogramming macrophage activation states during the established fibrotic phase.</p> Methods <p>In a rat model of bleomycin-induced pulmonary fibrosis, we characterized alveolar and interstitial macrophage profiles in control animals, in fibrotic animals, and after intratracheal transplantation of ATII cells performed on day 15 after bleomycin once fibrosis was established. Gene expression analyses were used to define macrophage activation profiles, while in vitro co-cultures of macrophages with ATII cells or fibroblasts assessed paracrine interactions and macrophage activation-state modulation. The CXCL12/CXCR4 signalling axis was further examined to explore potential mechanisms linking macrophage reprogramming to CXCR4⁺ cell dynamics, including recruitment of circulating CXCR4⁺ cells.</p> Results <p>Disease progression promoted a prominent profibrotic activation profile enriched in M2-associated markers in both alveolar and interstitial macrophages. ATII cell transplantation markedly reduced macrophage infiltration and shifted their activation toward a less profibrotic, more homeostatic profile. In vitro, soluble mediators released by healthy ATII cells contributed to modulation of macrophage activation states, restoring a less profibrotic activation profile. Reciprocal crosstalk between macrophages and fibroblasts was observed: fibrotic macrophages enhanced fibroblast activation, whereas macrophages from control lungs exerted antifibrotic effects. Notably, ATII cell transplantation normalised CXCL12/CXCR4 axis expression and reduced the number of circulating CXCR4⁺ cells, suggesting that modulation of this axis may limit the recruitment of circulating CXCR4⁺ cells and attenuate profibrotic signalling.</p> Conclusions <p>ATII cell transplantation ameliorates pulmonary fibrosis by restoring a less profibrotic immune microenvironment and modulating macrophage-fibroblast crosstalk. These effects are associated with reduced fibroblast activation and decreased accumulation of circulating CXCR4⁺ cells, consistent with attenuation of fibrotic responses.</p>

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Alveolar type II cell therapy ameliorates pulmonary fibrosis by reprogramming macrophage activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Raquel Guillamat-Prats,
  • Gemma Gay-Jordi,
  • Paula Duch,
  • Sabrina Gea-Sorlí,
  • Luis Ignacio Sanchez-Lopez,
  • Victor Ivo Peinado,
  • Anna Serrano-Mollar

摘要

Background

Alveolar type II (ATII) cell transplantation is a promising therapeutic strategy for idiopathic pulmonary fibrosis, although its underlying cellular mechanisms remain incompletely understood. Given that macrophage profibrotic activation is a key driver of fibrosis, we hypothesized that ATII cell therapy exerts antifibrotic effects by reprogramming macrophage activation states during the established fibrotic phase.

Methods

In a rat model of bleomycin-induced pulmonary fibrosis, we characterized alveolar and interstitial macrophage profiles in control animals, in fibrotic animals, and after intratracheal transplantation of ATII cells performed on day 15 after bleomycin once fibrosis was established. Gene expression analyses were used to define macrophage activation profiles, while in vitro co-cultures of macrophages with ATII cells or fibroblasts assessed paracrine interactions and macrophage activation-state modulation. The CXCL12/CXCR4 signalling axis was further examined to explore potential mechanisms linking macrophage reprogramming to CXCR4⁺ cell dynamics, including recruitment of circulating CXCR4⁺ cells.

Results

Disease progression promoted a prominent profibrotic activation profile enriched in M2-associated markers in both alveolar and interstitial macrophages. ATII cell transplantation markedly reduced macrophage infiltration and shifted their activation toward a less profibrotic, more homeostatic profile. In vitro, soluble mediators released by healthy ATII cells contributed to modulation of macrophage activation states, restoring a less profibrotic activation profile. Reciprocal crosstalk between macrophages and fibroblasts was observed: fibrotic macrophages enhanced fibroblast activation, whereas macrophages from control lungs exerted antifibrotic effects. Notably, ATII cell transplantation normalised CXCL12/CXCR4 axis expression and reduced the number of circulating CXCR4⁺ cells, suggesting that modulation of this axis may limit the recruitment of circulating CXCR4⁺ cells and attenuate profibrotic signalling.

Conclusions

ATII cell transplantation ameliorates pulmonary fibrosis by restoring a less profibrotic immune microenvironment and modulating macrophage-fibroblast crosstalk. These effects are associated with reduced fibroblast activation and decreased accumulation of circulating CXCR4⁺ cells, consistent with attenuation of fibrotic responses.