Role of NADPH oxidase in neuroinflammation

NADPH 氧化酶在神经炎症中的作用

基本信息

批准号：
7963971
负责人：
Francesca Bosetti
金额：
$ 15.32万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Given that NADPH oxidase has been implicated in the modulation of the alternatively-activated macrophage pathway, and that NADPH oxidase components are differentially expressed after lipopolysaccharide (LPS) injection in COX-1-/- and in COX-2-/- mice, we hypothesized that genetic deletion of the functional p47phox subunit of NADPH oxidase will attenuate the inflammatory response after LPS via reduction of oxidative stress and activation of the anti-inflammatory alternatively-activated macrophages/microglia. We found that p47phox-/- mice had reduced glial activation after LPS, as demonstrated by reduced immunostaining of microglial and astrocytic markers. Neutrophil infiltration was assessed by 7/4 immunostaining and was reduced in p47phox-/- compared to WT mice. Brain levels of MPO, another marker of neutrophils, were also reduced in p47phox-/- mice. Gene expression of TNF-alpha, a marker of classical activation, was decreased after LPS in p47phox-/- mice compared to WT mice, whereas expression of chitinase 3-like 3 (Ym1), a marker of the alternatively activated macrophage pathway, was increased. These data suggest that oxidative stress is an important component of neuroinflammatory damage and that the NADPH oxidase may play a role in switching the macrophage/microglia phenotype from an alternative, anti-inflammatory to a classical pro-inflammatory state. Thus, inhibition of NADPH oxidase may represent a novel anti-inflammatory approach.

Given that NADPH oxidase has been implicated in the modulation of the alternatively-activated macrophage pathway, and that NADPH oxidase components are differentially expressed after lipopolysaccharide (LPS) injection in COX-1-/- and in COX-2-/- mice, we hypothesized that genetic deletion of the functional p47phox subunit of NADPH oxidase will attenuate the inflammatory response LPS之后，通过减少氧化应激并激活抗炎的巨噬细胞/小胶质细胞。我们发现P47phox - / - 小鼠在LPS后降低了神经胶质活化，这是通过小胶质细胞和星形胶质细胞标记的免疫染色所证明的。通过7/4免疫染色评估中性粒细胞浸润，与WT小鼠相比，P47phox - / - 降低了中性粒细胞。在P47phox - / - 小鼠中，MPO的大脑水平也降低了。与WT小鼠相比，LPS在P47phox - / - 小鼠中LPS后TNF-Alpha的基因表达降低了，而几丁质酶3样3（YM1）的表达是替代激活的巨噬细胞途径的标志物（YM1）的表达。这些数据表明，氧化应激是神经炎性损伤的重要组成部分，而NADPH氧化酶可能在将巨噬细胞/小胶质细胞表型从替代方案（抗炎症）切换为经典促炎状态中发挥作用。因此，抑制NADPH氧化酶可能代表一种新型的抗炎方法。