Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses.
Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses.
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DOI：
10.1172/jci90848
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发表时间：
2017-09-01
期刊：
影响因子：
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通讯作者：
Walmsley SR
中科院分区：
文献类型：
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作者：
Sadiku P;Willson JA;Dickinson RS;Murphy F;Harris AJ;Lewis A;Sammut D;Mirchandani AS;Ryan E;Watts ER;Thompson AAR;Marriott HM;Dockrell DH;Taylor CT;Schneider M;Maxwell PH;Chilvers ER;Mazzone M;Moral V;Pugh CW;Ratcliffe PJ;Schofield CJ;Ghesquiere B;Carmeliet P;Whyte MK;Walmsley SR
完全激活的先天免疫细胞是有效应对感染所必需的，但它们的迅速失活和去除对于限制组织损伤至关重要。在这里，我们已经确定了脯氨酰羟化酶Phd 2在维持适当的，主要是嗜热链球菌介导的病原体清除和先天性免疫反应的解决之间的平衡的关键作用。我们证明了骨髓特异性Phd 2缺失导致对肺炎链球菌的过度炎症反应，增加了中性粒细胞运动性、功能性和存活率。这些增强的中性粒细胞反应依赖于糖酵解通量和糖原储备的增加。HIF-脯氨酰羟化酶抑制剂的全身给药复制了延迟炎症消退的Phd 2缺陷表型。总之，这些数据确定Phd 2作为在常氧条件下中性粒细胞中的主要HIF-羟化酶，并将糖酵解和糖原储存的内在调节与嗜中性粒细胞介导的炎症反应的消退联系起来。这些结果证明了靶向代谢途径在治疗炎性疾病中的治疗潜力。
Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF–prolyl hydroxylase inhibitor replicated the Phd2-deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to the resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease.