Natural killer cell dysfunction drives keloid pathogenesis

Keloids, characterized by excessive scar tissue resulting from abnormal wound healing, are primarily driven by hyperproliferative fibroblasts and overproduction of extracellular matrix. Although human natural killer (NK) cells are known for their role in inhibiting uncontrolled cell growth through cytokines like IFN-{gamma} and TNF-, they also produce amphiregulin (AREG), which paradoxically promotes cell proliferation and survival. The involvement of NK cells in keloid pathogenesis, however, remains largely unexplored. This study uncovers remarkable functional changes in NK cells within both lesional skin and the blood of keloid patients. In the skin, NK cell-produced IFN-{gamma} plays a pivotal role in limiting keloid progression by inducing fibroblast apoptosis and curbing excessive extracellular matrix production, while NK cell-derived AREG actively opposes these protective effects. Notably, TGF-{beta}-driven fibroblasts in keloid lesions further dampen NK cell IFN-{gamma} production, revealing a complex and dynamic cellular interplay. In the bloodstream of keloid patients, a distinct NK cell subset emerges, marked by elevated interferon-stimulated genes (ISGs) and diminished IFN-{gamma} production, which correlates with increased plasma IFN-{beta} levels. This elevated IFN-{beta} serves as a key initiating factor, driving NK cell exhaustion through impaired mitochondrial function and metabolic disruption. These findings highlight a critical mechanism underlying the functional abnormalities of keloid-associated NK cells and emphasize the influence of both local and systemic factors in shaping NK cell responses in keloid pathogenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/624588v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@7501f4org.highwire.dtl.DTLVardef@1d34de5org.highwire.dtl.DTLVardef@19f1c47org.highwire.dtl.DTLVardef@f98882_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIn the skin, NK cell-derived IFN-{gamma} is crucial for suppressing keloid fibroblast proliferation and extracellular matrix production. C_LIO_LIAREG from NK cells counteracts the inhibitory effects of IFN-{gamma} on keloid progression. C_LIO_LIIn the blood, elevated IFN-{beta} in keloid patients drives the emergence of ISG+NK cells with reduced IFN-{gamma} production. C_LIO_LIIFN-{beta} induces mitochondrial dysfunction and functional exhaustion in NK cells. C_LI