NK cells in hypoxic skin mediate a trade-off between wound healing and antibacterial defence

Abstract

During skin injury, immune response and repair mechanisms have to be coordinated for rapid skin regeneration and the prevention of microbial infections. Natural Killer (NK) cells infiltrate hypoxic skin lesions and Hypoxia-inducible transcription factors (HIFs) mediate adaptation to low oxygen. We demonstrate that mice lacking the Hypoxia-inducible factor (HIF)-1α isoform in NK cells show impaired release of the cytokines Interferon (IFN)-γ and Granulocyte Macrophage - Colony Stimulating Factor (GM-CSF) as part of a blunted immune response. This accelerates skin angiogenesis and wound healing. Despite rapid wound closure, bactericidal activity and the ability to restrict systemic bacterial infection are impaired. Conversely, forced activation of the HIF pathway supports cytokine release and NK cell-mediated antibacterial defence including direct killing of bacteria by NK cells despite delayed wound closure. Our results identify, HIF-1α in NK cells as a nexus that balances antimicrobial defence versus global repair in the skin.

LncRNA-COX2 inhibits Fibroblast Activation and Epidural Fibrosis by Targeting EGR1

“…Fibrosis is a progressive disease with excessive deposition of extracellular matrix (ECM) composed of fibrillar collagens, EDTA-fibronectin and SMA-stress fiber 27 , 36 - 39 . Sustained fibroblast proliferation, activation and migration, generally identified as wound healing response, continually happen after tissue injury 40 , 41 . Healing by epidural fibrosis instead of regeneration may place burden on spinal cord and nerve root after spinal surgery 42 .…”

Immune Cells in Cutaneous Wound Healing: A Review of Functional Data from Animal Models

“…NK cells are traditionally known for their ability to detect and kill tumor and virus-infected cells, but studies by Sobecki et al suggested that NK cells are also active during wound healing [ 95 ]. Depletion of NK cells in excisional wounds using anti-NK1.1 antibodies led to an early acceleration in wound closure via macroscopic measurement along with a corresponding increase in blood vessel density.…”

“…Conditional ablation of HIF-1a in cells expressing the gene encoding NKp46 (Ncr1, primarily expressed by NK cells) similarly lead to accelerated wound closure and an increase in vascularity, which may have been due to reduced production of IFN-γ and GM-CSF by HIF-1a-deficient NK cells. Interestingly, when challenged with group A Streptococcus , these mice had a dampened antimicrobial response [ 95 ]. Taken together, the results suggest that NK cells may not be beneficial for wound healing under normal circumstances, but that they likely aid in the response to infection.…”

Real‐time imaging of inflammation and its resolution: It’s apparent because it’s transparent*

“…Among the cell populations present in the skin at rest that contribute meaningfully to either tissue homeostasis or the wound healing response, there are as follows: commensal‐specific CD4 + or CD8 + T cells, 133‐135 Foxp3‐expressing regulatory T cells, 136,137 epidermal γδ T cells, 138‐142 skin‐resident memory T cells, 143‐145 Langerhans cells, 146‐148 dermal macrophages, 120,149‐152 and dendritic cells 153 . Following tissue damage, these resident cell populations are joined by neutrophils, monocyte‐derived macrophages, effector T cells, and NK cells, all of which can contribute to wound healing 154‐157 …”

“…153 Following tissue damage, these resident cell populations are joined by neutrophils, monocyte-derived macrophages, effector T cells, and NK cells, all of which can contribute to wound healing. [154][155][156][157] Is it possible to use the zebrafish untangle the web of leukocyte interactions involved during a wound healing response? While most of these cell populations are either infrequent or entirely absent in larval stage zebrafish, the skin composition in juvenile and adult fish is remarkably similar to mice and humans (Figure 1C).…”