What does this research mean for the field?

Mechanical stress promotes macrophage polarization toward the M2 phenotype, suppresses glycolytic metabolic reprogramming, and enhances pro-angiogenic function by activating the SOCS3/STAT3 pathway via the upregulation of Integrin Subunit Alpha D (ITGAD). Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The study aims to explore how mechanical stress affects macrophage polarization and metabolic processes in a pulmonary context.

June 14, 2026Open Access

Mechanical stress attenuates the metabolic reprogramming and M1 polarization of macrophages by upregulating integrin subunit alpha D

Key Points

The study aims to explore how mechanical stress affects macrophage polarization and metabolic processes in a pulmonary context.
Examined the effects of 10% amplitude mechanical stress on RAW264.7 cells.
Conducted transcriptomic analyses to assess changes in gene expression.
Explored the role of integrin subunit alpha D in the SOCS3/STAT3 signaling pathway.
Mechanical stress significantly downregulated M1 markers (CD86, IL-1β, iNOS, TNF-α) while upregulating M2 markers (TGF-β, CD206, IL-10).
Glycolytic enzymes (PKM2, GLUT1, PGK1, LDHA) were downregulated, leading to reduced lactate production and enhanced oxygen consumption.
Knockdown of ITGAD reversed the effects on macrophage polarization and metabolic reprogramming.

Abstract

We previously demonstrated that a novel growth-friendly system can alleviate pulmonary hypoplasia in piglets with early-onset scoliosis combined with thoracic insufficiency syndrome (EOS + TIS) by improving the mechanical microenvironment. Transcriptomic analyses indicated that mechanical stress (MS) may exert its effects by regulating immune responses and metabolic pathways. Building upon this foundation, the present study further investigates the implications of MS on macrophage polarization and metabolic reprogramming, as well as the underlying molecular mechanisms. In this study, MS at a 10% amplitude effectively downregulated M1-type markers (CD86, IL-1β, iNOS, TNF-α) in RAW264.7 cells, while upregulating M2-type markers (TGF-β, CD206, IL-10). Transcriptomic analysis further suggested that MS influences lung development by regulating glycolysis, metabolic reprogramming, and immune-related pathways. Further experiments demonstrated that the MS downregulated glycolytic enzymes (PKM2, GLUT1, PGK1, and LDHA), reduced lactate production and extracellular acidification rate, while enhancing oxygen consumption rate and promoting the tube-forming capacity of human umbilical vein endothelial cells, induced by conditioned media from RAW264.7 cells. Mechanistically, MS activated the SOCS3/STAT3 pathway by upregulating Integrin Subunit Alpha D (ITGAD) expression, thereby facilitating M2 polarization and suppressing glycolytic metabolic reprogramming in RAW264.7 cells. ITGAD knockdown reversed these implications. In conclusion, MS activates the SOCS3/STAT3 pathway by upregulating ITGAD, thereby promoting macrophage polarization toward the M2 phenotype, suppressing glycolytic metabolic reprogramming, and enhancing their pro-angiogenic function. This discovery reveals a novel mechanism of MS in the pulmonary microenvironment, providing a new molecular perspective for understanding the pathological processes of EOS + TIS-associated pulmonary dysplasia.

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