Kim Nancy D, Chou Richard C, Seung Edward, Tager Andrew M, Luster Andrew D
Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
J Exp Med. 2006 Apr 17;203(4):829-35. doi: 10.1084/jem.20052349. Epub 2006 Mar 27.
Neutrophil recruitment into tissue plays an important role in host defense and disease pathogenesis, including the inflammatory arthritides. A multitude of diverse chemoattractants have been implicated in neutrophil recruitment, suggesting that they have overlapping functions in mediating this critical biological response. However, here we demonstrate a unique, non-redundant role for the leukotriene B4 receptor BLT1 in mediating neutrophil recruitment into the joint in the K/BxN mouse model of inflammatory arthritis. We demonstrate that neutrophil expression of BLT1 was absolutely required for arthritis generation and chemokine production in this model, and that specific BLT1 inhibition reversed established disease. Adoptive transfer of wild-type (WT) neutrophils restored arthritis and chemokine production in BLT1(-/-) mice. Surprisingly, the primary effect of the transferred WT neutrophils into BLT1(-/-) mice was to promote the entry of endogenous BLT1(-/-) neutrophils into the joints of these mice. However, continued joint inflammation was dependent on the presence of WT neutrophils, indicating an ongoing specific requirement for BLT1-activated neutrophils in mediating BLT1(-/-) neutrophil recruitment by other chemoattractants. These experiments demonstrate that neutrophil BLT1 functions in a novel and essential non-cell-autonomous manner to enable the recruitment of additional neutrophils not expressing this receptor, thereby amplifying the inflammatory response in autoantibody-induced arthritis.
中性粒细胞募集到组织中在宿主防御和包括炎性关节炎在内的疾病发病机制中发挥着重要作用。多种不同的趋化因子与中性粒细胞募集有关，这表明它们在介导这种关键的生物学反应中具有重叠功能。然而，在此我们证明白三烯B4受体BLT1在炎性关节炎的K/BxN小鼠模型中介导中性粒细胞募集到关节中具有独特的、非冗余的作用。我们证明在该模型中，关节炎的发生和趋化因子的产生绝对需要中性粒细胞表达BLT1，并且特异性抑制BLT1可逆转已形成的疾病。野生型（WT）中性粒细胞的过继转移恢复了BLT1基因敲除（BLT1(-/-)）小鼠的关节炎和趋化因子产生。令人惊讶的是，将WT中性粒细胞转移到BLT1(-/-)小鼠中的主要作用是促进内源性BLT1(-/-)中性粒细胞进入这些小鼠的关节。然而，持续的关节炎症依赖于WT中性粒细胞的存在，这表明在介导其他趋化因子对BLT1(-/-)中性粒细胞的募集过程中，对BLT1激活的中性粒细胞存在持续的特定需求。这些实验表明，中性粒细胞BLT1以一种新的、必不可少的非细胞自主方式发挥作用，以促进募集不表达该受体的其他中性粒细胞，从而放大自身抗体诱导的关节炎中的炎症反应。
