Why standard stimulation protocols may encounter an immune barrier

In aesthetic medicine, fibroblasts are a primary target of skin-rejuvenation protocols. Device-based and injectable methods—including microneedling radiofrequency, lasers, poly-L-lactic acid, polynucleotides, and calcium hydroxylapatite—are intended to induce collagen synthesis. However, their results may be less predictable in mature skin.

A new study by a research group from Kumamoto University in Japan, led by Takehisa Suzuki and colleagues, suggests an unexpected explanation: IgG antibodies—immunoglobulin G—accumulate in the dermis with age and initiate an inflammatory cascade that suppresses collagen synthesis [1].

Chronic low-grade inflammation, or inflammaging, has long been recognized as an important factor in age-related skin changes [2]. However, the specific trigger that sustains this process in the dermis has remained unclear. Previous research showed that IgG accumulates with age in adipose tissue, the liver, kidneys, muscles, and the heart, where it activates macrophages and contributes to inflammation [3]. The new study examined whether a similar process occurs in the skin.

Study design: from human biopsies to a mouse model

The study was designed as a fundamental research project combining the analysis of human biomaterial, in vivo experiments in mice, and in vitro cellular experiments.

First, the authors examined normal skin biopsies from seven patients with skin cancer or epidermal cysts, ranging in age from 13 to 85 years. IgG was barely detectable in the dermis of the 13- and 17-year-old donors, whereas the five donors aged 44 years and older showed marked IgG accumulation. Age and IgG deposit intensity in the dermis were strongly correlated: Spearman’s correlation coefficient was r = 0.93 (p = 0.002).

To reproduce this phenomenon experimentally, young male C57BL/6N mice received intraperitoneal injections of total mouse IgG once a week for four weeks, at a dose of 3 mg per injection. The control group received phosphate-buffered saline. This increased circulating antibody levels and led to passive deposition in the dermal interstitium, resembling the pattern observed in older animals.

The cellular cascade: how IgG limits fibroblast function

IgG does not appear to act directly on fibroblasts. When dermal fibroblasts were cultured with IgG molecules, procollagen production did not change. A more complex immune pathway mediated the effect.

Administration of exogenous IgG to mice induced infiltration of the skin by inflammatory cells. Flow cytometry demonstrated a significant increase in monocytes/macrophages expressing F4/80 and T lymphocytes expressing CD3. The authors then reconstructed the molecular pathway step by step.

1. Macrophage activation. After entering the stroma, IgG binds to Fc gamma receptors (FcγR) on skin macrophages, promoting activation and increasing secretion of interleukin-12 (IL-12) and chemokines—including Cxcl10, Ccl3, and Ccl4—that attract additional immune cells to the skin.
2. T-cell involvement. IL-12 acts on dermal T cells and stimulates them to produce the pro-inflammatory cytokine interferon-gamma (IFN-γ). Neutralization of IL-12 with antibodies reduced IFN-γ induction, supporting the key role of this step in the cascade.
3. Suppression of collagen gene expression. The final target is the dermal fibroblast. IFN-γ activates the STAT1 signaling pathway in fibroblasts and selectively suppresses the transcription of genes encoding type I collagen (Col1a1) and type III collagen (Col3a1). Treatment of cultured fibroblasts with recombinant IFN-γ significantly reduced the expression of both genes.

Suppression of collagen synthesis by IFN-γ has also been described in earlier studies [4]. In addition, age-related changes in fibroblasts—including reductions in cell size and mechanical activity—may further limit collagen production [5]. Together, these processes may form a vicious cycle: IgG accumulation continuously fuels the inflammatory dermal microenvironment, shifting fibroblasts toward reduced biosynthetic activity.

Safety and associated reactions

Because this was a laboratory-based experimental study, the authors did not evaluate clinical safety criteria or adverse events. The authors did not report animal deaths or systemic reactions. The primary observed effect was a local inflammatory infiltrative process in the dermis.

Study limitations

The findings should be interpreted in light of the following limitations:

• Preclinical experimental format. The main body of evidence came from experiments using in vitro cell cultures and a mouse model in which the animals were artificially given total IgG at a dose of 3 mg once a week. Directly applying these experimental conditions and results to humans requires caution.
• Causal relationships in vivo were not confirmed. The authors demonstrated an association between IgG accumulation, macrophage activation, and increased IFN-γ expression in T cells. Still, they did not establish that this exact sequence of events occurs in a living organism. In addition, co-culture experiments cannot reproduce the full complexity of the dermal microenvironment.
• Small human sample. The skin samples came from only seven patients with skin cancer or epidermal cysts, rather than from healthy volunteers. Despite the strong positive correlation between age and IgG signal intensity in the dermis (Spearman’s correlation coefficient r = 0.93), the influence of the underlying conditions on IgG accumulation cannot be excluded.
• Unknown antibody specificity. The study used a total pool of serum IgG. It therefore remains unclear which specific antibodies, and which antigens they recognize, may accumulate in the dermis and participate in the inflammatory process described.
• The effect of aesthetic procedures was not studied. The study did not evaluate the skin’s response to device-based or injectable collagen-stimulating methods. Its findings therefore do not establish that IgG accumulation causes clinical resistance to these interventions or reduces their effectiveness.

Practical interpretation: a new perspective on collagen stimulation

Understanding this mechanism makes it possible to view age-related changes in the dermis not only as a consequence of reduced fibroblast activity, but also as a result of the inflammatory microenvironment surrounding these cells. When IgG accumulates in the dermis, macrophages activate, IL-12 and chemokine production increases, and T-cell activity and IFN-γ production are enhanced. In experiments using mouse skin cells, IFN-γ suppressed the expression of the collagen genes Col1a1 and Col3a1. These findings suggest that the state of the dermal immune microenvironment may influence how predictable the skin’s response to collagen-stimulating interventions is.

The following aspects are particularly relevant to clinical practice:

• Possible secondary resistance to collagen stimulation. If chronic inflammation involving macrophages, T cells, and IFN-γ persists in mature skin, fibroblasts may function under less favorable conditions for collagen synthesis. However, the study did not test the effectiveness of device-based or injectable procedures and does not establish clinical resistance to them.
• The need to consider the inflammatory background. The findings support a staged approach to managing patients with age-related skin changes. Before interventions intended to stimulate the dermis, it may be important to assess signs of inflammation and skin condition. However, this research did not study specific anti-inflammatory preparation protocols or methods aimed at improving microcirculation or lymphatic drainage, and these findings alone do not support evidence-based recommendations.
• Potential pharmacological targets. The authors identify IgG accumulation, its interaction with FcγR on macrophages, and the IL-12/IFN-γ signaling axis as areas for further investigation. They also discuss the possibility of influencing systemic IgG levels with drugs that target the neonatal Fc receptor (FcRn), including efgartigimod alfa. However, clinical studies have not yet confirmed the potential value of these approaches for preventing or correcting skin aging.
• The role of lifestyle remains a hypothesis. The authors refer to evidence that caloric restriction may reduce IgG accumulation in adipose tissue and discuss its possible relevance to age-related skin changes. However, the present study did not directly evaluate this effect in the skin.

Overall, the study suggests that the outcome of collagen stimulation should be considered not only in the context of the selected method and treatment intensity, but also of the immunological microenvironment of the dermis. At the same time, conclusions regarding secondary resistance, preliminary anti-inflammatory preparation, and the use of agents that affect IgG or FcRn remain promising hypotheses. Further in vivo and clinical studies are needed to confirm the causal relationship between IgG accumulation, dermal inflammation, and the skin’s response to aesthetic interventions.

References

1. Suzuki T., Horiguchi H., Yamamura S. et al. Aging-related IgG accumulation promotes skin inflammation. J Invest Dermatol 2026; 9: S0022-202X(26)02806-X.
2. Pilkington S.M., Bulfone-Paus S., Griffiths C.E.M., Watson R.E.B. Inflammaging and the skin. J Invest Dermatol 2021; 141(4): 1087–1095.
3. Yu L., Wan Q., Liu Q. et al. IgG is an aging factor that drives adipose tissue fibrosis and metabolic decline. Cell Metab 2024; 36(4): 793–807.e5.
4. Granstein R.D., Flotte T.J., Amento E.P. Interferons and collagen production. J Invest Dermatol 1990; 95(6): S75–80.
5. Fisher G.J., Shao Y., He T. et al. Reduction of fibroblast size/mechanical force down-regulates TGF-β type II receptor: Implications for human skin aging. Aging Cell 2016; 15(1): 67–76.