Meers Garrit K, Bohnenberger Hanibal, Reichardt Holger M, Lühder Fred, Reichardt Sybille D
Institute for Cellular and Molecular Immunology, University Medical Center Goettingen, Göttingen, Germany.
Institute of Pathology, University Medical Center Goettingen, Göttingen, Germany.
PLoS One. 2018 Jan 11;13(1):e0190846. doi: 10.1371/journal.pone.0190846. eCollection 2018.
Inflammatory bowel disease (IBD) is a highly prevalent intestinal disorder for which no cure exists. Currently, the standard first-line treatment of IBD consists of systemic glucocorticoid (GC) application, even though therapy can be complicated by unresponsiveness or adverse effects. In view of the importance of macrophages and neutrophils for the pathogenesis of IBD we set out to define the relevance of these cell types as targets of GC using the mouse model of DSS-induced colitis. We found that the disease did not resolve in GRlysM mice lacking the GC receptor (GR) in myeloid cells after removal of the chemical insult. While clinical symptoms and tissue damage in the colon ameliorated again in GRflox mice, the disease further aggravated in GRlysM littermates. The observed difference coincided with an increased abundance of macrophages in inflammatory infiltrates in the colon of mutant mice whereas neutrophil and T cell numbers were similar. Concomitantly, systemic IL-6 secretion and mRNA levels of pro-inflammatory cytokines in the colon were elevated in GRlysM mice and gene expression of scavenger receptors and IL-10 was diminished. Taken together, our results reveal an important role of myeloid cells as targets of GC in DSS-induced colitis and probably in IBD in humans as well.
炎症性肠病（IBD）是一种高度流行的肠道疾病，目前尚无治愈方法。目前，IBD的标准一线治疗包括全身应用糖皮质激素（GC），尽管治疗可能会因无反应或不良反应而变得复杂。鉴于巨噬细胞和中性粒细胞在IBD发病机制中的重要性，我们着手利用葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型来确定这些细胞类型作为GC靶点的相关性。我们发现，在去除化学刺激后，缺乏髓系细胞糖皮质激素受体（GR）的GRlysM小鼠的疾病并未得到缓解。虽然GRflox小鼠的结肠临床症状和组织损伤再次改善，但GRlysM同窝小鼠的疾病进一步加重。观察到的差异与突变小鼠结肠炎症浸润中巨噬细胞丰度增加一致，而中性粒细胞和T细胞数量相似。与此同时，GRlysM小鼠的全身IL-6分泌和结肠中促炎细胞因子的mRNA水平升高，清道夫受体和IL-10的基因表达降低。综上所述，我们的结果揭示了髓系细胞作为GC靶点在DSS诱导的结肠炎中以及可能在人类IBD中发挥的重要作用。
