The mechanism of innate inflammation in response to cell death and it's contribution to the pathogenesis of rheumatoid arthritis

细胞死亡，特别是坏死性细胞死亡，诱导急性炎症。据推测，这种急性反应是许多病理条件，包括自身免疫性疾病的基础，但危险信号，以诱发炎症或负责中性粒细胞募集的关键途径的分子机制还没有得到很好的研究。在我们的系统中，炎症到细胞死亡取决于IL-1。IL-1被转录为不成熟的蛋白质，并且需要被胱天蛋白酶-1切割。在这里，我们确定了一种新的分子途径，细胞死亡诱导的炎症，这是依赖于IL-1，但不依赖于Caspase-1。此外，我们确定了组织蛋白酶C作为参与这种体内Caspase-1非依赖性途径的关键分子之一。已知组织蛋白酶C可使中性粒细胞宁静蛋白酶成熟，包括蛋白酶3，蛋白酶3显示出在体外使IL-1成熟的能力。

Cell death, especially necrotic cell death, induces acute inflammation. It is supposed that this acute responses underlie many pathological conditions including autoimmune diseases, but the molecular mechanisms of the danger signals to evoke inflammation or the key pathways responsible for neutrophil recruitment are not well studied.We investigated the molecular mechanisms responsible for inducing inflammatory responses to necrotic cells in vivo. In our system the inflammation to cell death depends on IL-1. IL-1 is transcribed as an immature protein and requires cleavage by Caspase-1. Here we identified a novel molecular pathway to cell death-induced inflammation that is dependent on IL-1, but not on Caspase-1. IN addition, we identified Cathepsin C as one of the key molecules involved in this Caspase-1 independent pathway in vivo. Cathepsin C is known to maturate neutrophil serene proteases including proteinase 3 that was shown to have ability to maturate IL-1 in vitro.