Therapy for steatohepatitis: Do macrophages hold the clue?
Therapy for steatohepatitis: Do macrophages hold the clue?
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脂肪性肝炎的治疗：巨噬细胞掌握线索吗？
DOI：
10.1002/hep.29630
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Anania,FrankA
中科院分区：
文献类型：
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作者：
Raeman,Reben;Anania,FrankA
单核细胞和巨噬细胞是组织损伤、再生和纤维化的关键调节因子。（1，2）虽然它们在非酒精性脂肪性肝炎（NASH）发病机制中的作用没有争议，（3）它们的功能模糊性和表型多样性使我们从治疗角度靶向这些细胞的能力变得复杂。在本期《肝脏学》杂志中，Krenkel及其同事推进了我们对NASH发病机制中巨噬细胞异质性功能差异的理解。(4)使用NASH的人类组织和常规小鼠模型，这些研究人员优雅地证明了骨髓来源的巨噬细胞，趋化因子（CC基序）受体2（CCR 2+）巨噬细胞的特定子集的参与，这些巨噬细胞通过库普弗细胞（KC），肝星状细胞和肝细胞分泌的趋化因子（CC基序）配体2被召唤到肝脏。肝脏巨噬细胞或KC（CD 11b +F4/80 hiLy 6C-）、单核细胞衍生的巨噬细胞（MoMF; CD 11b +F4/80 loLy 6CLo）和骨髓衍生的单核细胞是NASH肝脏炎症和纤维化的主要介质。(3)KC来自胚胎祖细胞，并通过自我更新在肝脏中维持。(5)然而，单核细胞从循环中募集到受损的肝脏中。单核细胞的两个主要亚群被募集到NASH中的损伤的肝脏中，经典或炎性单核细胞（小鼠中的Ly 6ChiCCR 2 + CX 3CR 110，人中的CD 14 + CD 16+）和非经典、组织驻留或修复单核细胞（小鼠中的Ly 6ChiCCR 2 + CX 3CR 1hi，人中的CD 14 + CD 16 ++）。（3，6）Ly 6 Chi经典单核细胞主要以趋化因子（CC基序）配体2/CCR 2依赖性方式募集，而CX 3CL 1/CX 3CR 1轴驱动Ly 6 Clo非经典单核细胞的募集。（6，7）Ly 6Chi经典单核细胞产生MoMF以及Ly 6Clo单核细胞，但这取决于局部炎症环境（图1）。（1，2）由于KC、MoMF和单核细胞对炎症反应的持续时间及其消退至关重要，因此人们对描绘这些参与者在NASH的肝脏炎症、纤维化和修复中的具体任务非常感兴趣。Krenkel等人目前研究的科学前提。(4)基于人类数据，其证明在患有NASH和纤维化（3期）的患者以及诊断为患有NASH和肝硬化（4期）的患者中CCR 2+巨噬细胞的数量显著更大。这些数据支持作者使用赛尼克韦罗（CVC; Tobira）预防CCR 2 + MoMF肝浸润的基本原理，赛尼克韦罗是一种口服、每日一次的CCR 2/CCR 5双重拮抗剂，在人体中具有纳摩尔效力和长半衰期。(8)CVC的2b期临床试验（NCT 02217475）现已接近完成（8），该研究的结果最近在该杂志上报道。(9)2b期数据显示，CVC治疗1年后，纤维化评分改善一个或多个阶段，脂肪性肝炎没有恶化。虽然CVC降低了炎症的全身标志物，包括白细胞介素1和6、纤维蛋白原和C反应蛋白，但在接受安慰剂或CVC的患者之间没有观察到肝活检的炎症评分的差异。(9)因此，该试验未能满足任何一项主要研究
Monocytes and macrophages are key regula-tors of tissue injury, regeneration, and fibrosis.(1, 2) While their role in nonalcoholic steatohepatitis (NASH) pathogenesis is not disputed,(3) their functional ambiguity and phenotypical diversity complicate our ability to target such cells from a therapeutic perspective. In this issue of HEPATOLOGY, Krenkel and colleagues advance our understanding of the functional differences in macrophage heterogeneity in NASH pathogenesis.(4) Using human tissue and conventional mouse models for NASH, these investigators elegantly demonstrate involvement of a specific subset of bone marrow–derived macrophages, chemokine (CC motif) receptor 2 (CCR2+) macrophages, that are summoned to the liver by chemokine (CC motif) ligand 2 secreted by Kupffer cells (KCs), hepatic stellate cells, and hepatocytes. Liver-resident macrophages or KCs (CD11b+F4/80hiLy6C–), monocyte-derived macrophages (MoMFs; CD11b+F4/80loLy6CLo), and bone marrow–derived monocytes are primary mediators of hepatic inflammation and fibrosis in NASH.(3) KCs arise from embryonic progenitors and are sustained in the liver through self-renewal.(5) Monocytes, however, are recruited from the circulation into the injured liver. Two major subsets of monocytes are recruited into the injured liver in NASH, classical or inflammatory monocytes (Ly6ChiCCR2+CX3CRllo in mice, CD14+CD16J in humans) and nonclassical, tissueresident, or repair monocytes (Ly6CloCCR2JCX3CR1hi in mice, CD14+CD16++ in humans).(3, 6) Ly6Chi classical monocytes are recruited predominantly in a chemokine (CC motif) ligand 2/CCR2-dependent manner, while the CX3CL1/CX3CR1 axis drives recruitment of Ly6Clo nonclassical monocytes.(6, 7) Ly6Chi classical monocytes give rise to MoMFs as well as Ly6Clo monocytes, but this is dependent on the local inflammatory milieu (Fig. 1).(1, 2) Because KCs, MoMFs, and monocytes are central to the duration of the inflammatory response and its resolution, there is substantial interest in delineating the specific tasks for these players in hepatic inflammation, fibrosis, and repair in NASH. The scientific premise of the current study by Krenkel et al.(4) is based on human data that demonstrate a significantly greater number of CCR2+ macrophages in patients with NASH and fibrosis (stage 3) as well as in patients diagnosed with NASH and cirrhosis (stage 4). These data support the authors’ rationale to prevent hepatic infiltration of CCR2+ MoMFs using cenicriviroc (CVC; Tobira), an oral, once-daily dual CCR2/CCR5 antagonist with nanomolar potency and a long half-life in humans.(8) A phase 2b clinical trial (NCT02217475) is now nearing completion with CVC,(8) and results of the study were recently reported in this journal.(9) The phase 2b data reveal improvement in the fibrosis score by one or more stage with no worsening of steatohepatitis after 1 year of CVC treatment. While CVC reduced systemic markers of inflammation including interleukins 1 and 6, fibrinogen, and C-reactive protein, no difference in the inflammatory scores on liver biopsy between patients receiving placebo or CVC was observed.(9) Thus, the trial failed to meet either of the primary study