Bourinet Manon, Vieira Elodie, Rousseau Déborah, Bonnafous Stéphanie, Soysouvanh Fréderic, Strazzulla Axelle, Elliot Coline, Patouraux Stéphanie, Leclère Pierre S, Moskalevska Iryna, Cherfils-Vicini Julien, Tulic Meri K, Mack Matthias, Bailly-Maitre Béatrice, Orian-Rousseau Véronique, Iannelli Antonio, Belmer Arnauld, Tran Albert, Anty Rodolphe, Gual Philippe, Luci Carmelo
Université Côte d'Azur, INSERM U1065, C3M, Nice, France.
Université Côte d'Azur, CHU, INSERM U1065, C3M, Nice, France.
Liver Int. 2025 Sep;45(9):e70299. doi: 10.1111/liv.70299.
Innate lymphoid cells (ILCs) play pivotal roles in inflammation and fibrosis, which are key features of chronic liver diseases. The contribution of group 1 ILCs, including natural killer (NK) cells and helper-like ILC1s, to liver inflammation during steatohepatitis and metabolic dysfunction-associated steatotic liver diseases (MASLD) is still a matter of debate and requires further investigation.
We engineered a mouse model of specific deficiency of CD44 in group 1 ILCs and challenged mice with diet-induced obesity and MASLD or diet-induced steatohepatitis. We performed in vitro studies and co-cultured LPS-stimulated liver NK cells with hepatocytes and macrophages to analyse the inflammatory response.
As group 1 ILCs expressed the cell surface molecule CD44, its specific targeting was used to investigate if CD44 could affect the development of liver inflammation. Here, we found that CD44 deficiency in group 1 ILCs was sufficient to decrease the absolute number of hepatic NKp46 ILCs, NK cells and ILC1s in chow diet and in response to diet induced-MASLD or steatohepatitis. CD44 deficiency in group 1 ILCs aggravated liver complications by exacerbating hepatic injury, inflammation, and fibrosis, which was also associated with inflammatory and osteopontin macrophages accumulation. The absence of CD44 in NK cells enhanced their inflammatory phenotypes in response to LPS, which in turn triggered release of pro-inflammatory mediators by hepatocytes and macrophages.
Our findings reveal a novel role for CD44 in regulating the dynamics of group 1 ILCs, which in turn affects steatohepatitis and MASLD development.
固有淋巴细胞（ILCs）在炎症和纤维化过程中发挥关键作用，而炎症和纤维化是慢性肝病的关键特征。1型固有淋巴细胞，包括自然杀伤（NK）细胞和辅助样ILC1s，在脂肪性肝炎和代谢功能障碍相关脂肪性肝病（MASLD）期间对肝脏炎症的作用仍存在争议，需要进一步研究。
我们构建了1型固有淋巴细胞特异性缺乏CD44的小鼠模型，并用饮食诱导的肥胖和MASLD或饮食诱导的脂肪性肝炎对小鼠进行挑战。我们进行了体外研究，并将脂多糖刺激的肝脏NK细胞与肝细胞和巨噬细胞共培养，以分析炎症反应。
由于1型固有淋巴细胞表达细胞表面分子CD44，因此利用其特异性靶向来研究CD44是否会影响肝脏炎症的发展。在此，我们发现，在正常饮食以及对饮食诱导的MASLD或脂肪性肝炎的反应中，1型固有淋巴细胞中CD44的缺乏足以减少肝脏NKp46固有淋巴细胞、NK细胞和ILC1s的绝对数量。1型固有淋巴细胞中CD44的缺乏通过加剧肝损伤、炎症和纤维化而加重肝脏并发症，这也与炎症性和骨桥蛋白巨噬细胞的积累有关。NK细胞中CD44的缺失增强了它们对脂多糖的炎症表型，进而触发肝细胞和巨噬细胞释放促炎介质。
我们的研究结果揭示了CD44在调节1型固有淋巴细胞动态中的新作用，这反过来又影响脂肪性肝炎和MASLD的发展。
