Blood research · 2025
STING-Dependent spontaneous platelet adhesion potentiates NK cell proinflammatory responses in pediatric crohn's disease.
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Lv Jiajia, Zhang Meng, Wang Xinqiong, Xu Xu, Li Jia, Wang Junqi, Xu Chundi, Yu Yi, Cao Wei, Xiao Yuan
Аннотация
BACKGROUND: Platelets are hypothesized to participate in the pathogenesis of Crohn's disease (CD) by interacting with other inflammatory cells such as natural killer (NK) cells. In this study, we aimed to evaluate the effects of platelet-NK cell interactions, both in vitro and in vivo, along with the corresponding mechanisms.
METHODS: Clinical data were collected from patients with CD and IL-10 receptor alpha (IL-10RA) mutations, with the control group being comprised of patients with functional abdominal pain. Platelets and NK cells from the patients' colon tissues were immunostained. Dextran sulfate sodium (DSS)-induced colitis models using wild type (WT) and Stimulator of Interferon Genes knockout (STING-/-) mice were evaluated. Both purified CD41+ and CD41-NK cells were cultured with IL-2 and STING inhibitor C-176 to determine in vitro cell proliferation and Type 3 (T3) cytokine expression. Flow cytometry, enzyme-linked immunosorbent assays, and RT-PCR were used to assess the expression of CD41, IL-17, and adhesion-related molecules in mouse and human NK cells.
RESULTS: Circulating and intestinal platelets were higher in patients with IL-10RA mutations compared to CD patients and correlated positively with serum cytokines, fecal calprotectin (FCP), and blood NK cells. Gut inflammation and T3 cytokine expression in NK cells were significantly lower in STING-/- mice compared to WT mice. Platelet-adherent NK cells showed significant proliferation and enhanced T3 cytokine expression, whereas STING inhibition markedly suppressed platelet adhesion, cell proliferation, and T3 cytokine expression. The naïve lung tissue of mice also displayed similar platelet-NK cell interactions. Platelet adhesion on NK cells led to higher CD24 expression compared to CD41-NK cells and we observed relatively higher CD24 in the NK cells from patients with IL-10RA mutations compared to patients with CD.
CONCLUSIONS: Spontaneous platelet adhesion via STING signaling potentiates NK cell proinflammatory response in CD.
METHODS: Clinical data were collected from patients with CD and IL-10 receptor alpha (IL-10RA) mutations, with the control group being comprised of patients with functional abdominal pain. Platelets and NK cells from the patients' colon tissues were immunostained. Dextran sulfate sodium (DSS)-induced colitis models using wild type (WT) and Stimulator of Interferon Genes knockout (STING-/-) mice were evaluated. Both purified CD41+ and CD41-NK cells were cultured with IL-2 and STING inhibitor C-176 to determine in vitro cell proliferation and Type 3 (T3) cytokine expression. Flow cytometry, enzyme-linked immunosorbent assays, and RT-PCR were used to assess the expression of CD41, IL-17, and adhesion-related molecules in mouse and human NK cells.
RESULTS: Circulating and intestinal platelets were higher in patients with IL-10RA mutations compared to CD patients and correlated positively with serum cytokines, fecal calprotectin (FCP), and blood NK cells. Gut inflammation and T3 cytokine expression in NK cells were significantly lower in STING-/- mice compared to WT mice. Platelet-adherent NK cells showed significant proliferation and enhanced T3 cytokine expression, whereas STING inhibition markedly suppressed platelet adhesion, cell proliferation, and T3 cytokine expression. The naïve lung tissue of mice also displayed similar platelet-NK cell interactions. Platelet adhesion on NK cells led to higher CD24 expression compared to CD41-NK cells and we observed relatively higher CD24 in the NK cells from patients with IL-10RA mutations compared to patients with CD.
CONCLUSIONS: Spontaneous platelet adhesion via STING signaling potentiates NK cell proinflammatory response in CD.