Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria
Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria.
EMBO Mol Med. 2014 Jun;6(6):810-20. doi: 10.1002/emmm.201303415. Epub 2014 Apr 6.
Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate-mediated early control of infection, the systemic inflammatory response was repressed in fibrate-treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS-induced phosphorylation of ERK. This results in a decrease of G protein-coupled receptor kinase-2 expression, thereby inhibiting the LPS-mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis.
细菌败血症导致高死亡率，迫切需要新的治疗方法来控制感染。在这里，我们研究了纤维酸酯在治疗细菌性败血症中的治疗潜力，并研究了它们对固有免疫的影响。纤维酸酯显著提高了感染鼠伤寒沙门氏菌的败血症小鼠的存活率，这与中性粒细胞大量涌入感染部位导致入侵细菌迅速清除相平行。由于纤维酸酯介导的早期感染控制，纤维酸酯治疗的小鼠的全身炎症反应受到抑制。从机制上讲，我们发现纤维酸酯通过阻止 LPS 诱导的 ERK 磷酸化来维持鼠中性粒细胞的趋化性。这导致 G 蛋白偶联受体激酶-2 的表达减少，从而抑制了 LPS 介导的 CXCR2 下调，CXCR2 是中性粒细胞募集的关键趋化因子受体。因此，应用合成的 CXCR2 抑制剂完全消除了纤维酸酯在体内败血症中的保护作用。我们的研究结果揭示了纤维酸酯在固有免疫和宿主对感染的反应中的新功能，并表明纤维酸酯作为细菌败血症的一种有前途的辅助治疗方法。
