Trained immunity in skin infections: Macrophages and beyond

  1. Vitka Gres
  2. Merve Göcer
  3. Julia Kolter
  4. Philipp Henneke  Is a corresponding author
  1. Institute for Infection Prevention and Control, Medical Center and Faculty of Medicine, University of Freiburg, Germany
  2. Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, Germany
  3. Faculty of Biology, University of Freiburg, Germany
  4. Institute for Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, Germany
3 figures

Figures

Metabolites of the TCA cycle involved in trained immunity.

ACOD1 - aconitate decarboxylase, encoded by Immune responsive gene 1 (IRG1). SDH – succinate dehydrogenase, KDM5 - Lysine-specific demethylase 5.

Innate memory formation in S. aureus skin infection.

In homeostatic mouse skin, tissue resident (TRMΦ) represent the largest innate immune cell population. Monocytes differentiate into macrophages (MDMΦ) over time. Some immune cells of the skin are not represented in this scheme, for example CD4 T cells and γδ T cells. During S. aureus skin infection, neutrophils and monocytes rapidly migrate to the site of infection, where abscess formation typically occurs. In some cases, S. aureus can disseminate into the circulation, leading to the reprogramming of HSCs in the bone marrow. Tissue-resident MΦ (TRMΦ) at the infection site often undergo necrosis, while infiltrating monocytes differentiate into macrophages (MDMΦ) at an accelerated rate to replenish the population. Upon reinfection, there is an enhanced recruitment of neutrophils, MΦ, and DCs compared to naïve controls, accompanied by elevated levels of inflammatory cytokines and chemokines, including IL-22, CXCL9, CXCL1, TNF, and IFN-γ. The trained phenotype in tissue-resident MΦ wanes over time, as they get gradually replaced by incoming, non-trained monocytes, unless the central innate memory is established, which involves the epigenetic programming of monocyte progenitors in the bone marrow.

Epigenetic and metabolic reprogramming of dermal MΦ in S. aureus infection.

MΦ detect S. aureus through various pattern recognition receptors (PRRs), such as TLR2 and endosomal TLRs (8, 9, 13). Infection causes a reduction in OXPHOS and an increase in glycolysis, leading to the accumulation of lactate and certain TCA cycle metabolites (e.g., itaconate, succinate). Succinate stabilizes HIF-1α, which then triggers the expression of glycolytic genes early in the infection. GM-CSF signaling bypasses the reliance on HIF-1α. DNA methylation and chromatin unfolding enable rapid transcription of inflammatory mediators. Once the infection is cleared, some of the macrophage alterations remain, allowing for an altered immune response during subsequent infections.

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  1. Vitka Gres
  2. Merve Göcer
  3. Julia Kolter
  4. Philipp Henneke
(2025)
Trained immunity in skin infections: Macrophages and beyond
eLife 14:e106688.
https://doi.org/10.7554/eLife.106688