Neutrophil extracellular traps impair regeneration

Abstract

Fibrosis is a major health burden across diseases and organs. To remedy this, we study wound‐induced hair follicle neogenesis (WIHN) as a model of non‐fibrotic healing that recapitulates embryogenesis for de novo hair follicle morphogenesis after wounding. We previously demonstrated that TLR3 promotes WIHN through binding wound‐associated dsRNA, the source of which is still unclear. Here, we find that multiple distinct contexts of high WIHN all show a strong neutrophil signature. Given the correlation between neutrophil infiltration and endogenous dsRNA release, we hypothesized that neutrophil extracellular traps (NETs) likely release nuclear spliceosomal U1 dsRNA and modulate WIHN. However, rather than enhance regeneration, we find mature neutrophils inhibit WIHN such that mice with mature neutrophil depletion exhibit higher WIHN. Similarly, Pad4 null mice, which are defective in NET production, show augmented WIHN. Finally, using single‐cell RNA sequencing, we identify a dramatic increase in mature and activated neutrophils in the wound beds of low regenerating Tlr3−/− mice. Taken together, these results demonstrate that although mature neutrophils are stimulated by a common pro‐regenerative cue, their presence and NETs hinder regeneration.

Synergism between obesity and HFpEF on neutrophils phenotype and its regulation by adipose tissue‐molecules and SGLT2i dapagliflozin

“…Moreover, since dapagliflozin reduces the anaerobic glycolysis, 36 main metabolism on activated neutrophils, and CD11B expression levels, might suggest a protective role against inflammation response on patients with obesity and HFpEF progression 37 . Moreover, the higher presence of RNase2 and 3 in neutrophils from obese patients, which are involved on extracellular matrix remodelling, 38 might drive to an impaired myocardial regeneration 38,39 . Although further studies are needed, the results of this study contribute to understand the protective dapagliflozin mechanisms underlying HF 40 …”

“… 37 Moreover, the higher presence of RNase2 and 3 in neutrophils from obese patients, which are involved on extracellular matrix remodelling, 38 might drive to an impaired myocardial regeneration. 38 , 39 Although further studies are needed, the results of this study contribute to understand the protective dapagliflozin mechanisms underlying HF. 40 …”

Tracing immune cells around biomaterials with spatial anchors during large-scale wound regeneration

“…In contrast, type-2 anti-inflammatory macrophages might play an essential role in wound fibrosis by promoting fibrotic fibroblast activation and collagen cross-linking 3 via fibrotic cytokines such as transforming growth factor–beta (TGF-β) 13 and RELMα 14 or chronic phagocytosis activity 4 at a later stage. Although the role of macrophages in pathogen clearance and tissue fibrosis 15 has long been stressed, only recently have the T lymphocytes been more thoroughly investigated. In addition to γδ T cells that induce HF neogenesis through the secretion of fibroblast growth factor 9 (Fgf9) 6 , the adaptive T cells are being explored to gain more understanding of its role in regulating macrophage polarization and, thus, wound regeneration 2 .…”

Skin Wound Healing: Of Players, Patterns, and Processes

“…The process further integrates M2 macrophages, which express growth factors important for the regulation of the hair cycle and hair growth, such as fibroblast growth factor (FGF)-2 and insulin-like growth factor (IGF)-2 [42]. However, the WHIN process, and thus to some extent general regeneration, appears to be susceptible to inhibition by mature neutrophils because mice deficient in mature neutrophils have higher WIHN [43].…”

“…However, NET production is not always accompanied by a positive effect. It has been shown that impaired NET production leads to increased WIHN, indicating that neutrophils may even hinder regeneration in the later course of wound healing [43].…”