PREreview of Fibroblast-encoded inflammatory memory orchestrates recurrent skin inflammation via NNMT-dependent metabolic remodeling

Major issues

1. The generalizability of the findings across inflammatory diseases is not fully established. The manuscript suggests that NNMT-driven fibroblast memory represents a common stromal program; however, evidence in other inflammatory diseases remains mainly correlative. Functional validation in additional disease models is needed.

2. The relationship between fibroblast inflammatory memory and immune-cell memory requires deeper clarification. The study highlights fibroblasts as regulators of relapse through SASP and Trm maintenance, but how fibroblast memory interacts with immune memory programs such as tissue-resident memory T cells and trained immunity remains unclear.

3. The mechanism of inflammatory memory formation may involve multiple interconnected pathways. The involvement of complement signaling (C3/C3aR), metabolic reprogramming, and epigenetic remodeling suggests multiple regulatory layers. The contribution and hierarchy of these pathways require further clarification.

4. Therapeutic strategies targeting inflammatory memory need further validation. Complement inhibition, metabolic modulation, NNMT targeting, and dietary metabolites represent potential approaches, but their long-term effects and specificity require further investigation.

5. The maintenance of persistent fibroblast activation after inflammation resolution requires further explanation. Although fibroblasts acquire SASP and metabolic changes, the signals responsible for maintaining this long-term inflammatory memory state remain unclear.

Minor issues

1. More clarification is needed on how fibroblast metabolic changes regulate inflammatory gene expression. The link between glycolysis, oxidative phosphorylation, SAM metabolism, and persistent inflammatory transcription should be explored further.

2. The interaction between fibroblasts and immune cells could be discussed in more detail. The mechanisms by which fibroblast-derived signals regulate Trm cells, γδ T cells, and other immune populations require further clarification.

Competing interests

The author declares that they have no competing interests.

Use of Artificial Intelligence (AI)

The author declares that they used generative AI to come up with new ideas for their review.