Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge.
Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge.
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作者：
Norden DM;Trojanowski PJ;Villanueva E;Navarro E;Godbout JP
外周免疫系统的激活引起中枢神经系统的协调反应。这种免疫大脑通讯的关键是神经胶质细胞，小胶质细胞和星形胶质细胞，在大脑中解释和传播影响生理和行为反应的炎症信号。神经胶质生物学的一个问题是，仅用形态学分析来报告神经胶质的激活状态。因此，我们的目的是比较体内免疫（脂多糖，LPS）挑战后神经胶质特异性mRNA和形态学特征的行为反应。在这里，LPS刺激引起了立即但短暂的疾病反应，运动和社会互动减少。与主动生病行为（2-12h）相对应，炎症细胞因子mRNA在富集的小胶质细胞和星形胶质细胞中表达升高。虽然促炎细胞因子在LPS后2-4小时达到峰值，但星形胶质细胞细胞因子和趋化因子的诱导延迟，并在12小时达到峰值。然而，在这2-12小时内，未检测到小胶质细胞（Iba-1+）和星形胶质细胞（GFAP+）的形态学改变。LPS作用后24和48小时，Iba-1免疫反应性和去分枝小胶质细胞明显增加，但与激活的消退期相对应。LPS处理后星形胶质细胞未见形态学改变。此外，四次重复注射LPS后，胶质细胞因子的表达与形态学无关。事实上，与急性LPS刺激相比，重复LPS刺激与免疫和行为耐受性以及炎症性小胶质细胞谱有关。总的来说，胶质细胞因子表达的诱导是顺序的，与主动疾病行为一致，并且在LPS刺激后Iba-1或GFAP免疫反应性增加之前。
Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2–12h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although pro-inflammatory cytokine expression in microglia peaked 2–4 h after LPS, astrocyte cytokine and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1+) and astrocytes (GFAP+), however, were undetected during this 2–12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared to acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge.