The Guts of HIV: Innate Immune Dysregulation as a Central Mechanism of Gastrointestinal and Liver Disease in HIV-1-infected Individuals

 描述(申请人提供)：在接受抗逆转录病毒疗法(ART)治疗的HIV-1感染者中，肝病(LD)已上升为发病率和死亡率的主要原因。越来越多的证据表明，HIV-1通过全身炎症改变和加速了推动LD的病理过程；然而，中性粒细胞和先天免疫失调在这些过程中的作用尚未得到评估。这一应用表明，肠道相关淋巴组织(GALT)和肝脏中巨噬细胞和中性粒细胞数量的变化所介导的先天免疫失调在HIV-1疾病的进展中起着基础性作用。中性粒细胞是体内最丰富的免疫细胞群，专门用于敏感地检测入侵的微生物和病毒病原体。HIV-1和SIV感染的高尔特上皮损伤在时间和空间上都与中性粒细胞的大量积累有关，中性粒细胞直接导致粘膜损伤。IL-17是中性粒细胞功能的主要调节者，与IL-10一起诱导抗炎巨噬细胞，通过胞吐清除凋亡的中性粒细胞，促进局部和全身炎症的愈合和消退。这一建议的第一个基本假设是，HIV-1感染者GALT中产生IL-17的细胞的耗尽阻止了抗炎泡泡细胞组织巨噬细胞的诱导，并导致两极分化为促炎表型。这会导致中性粒细胞的积聚，导致中性粒细胞发生网织红细胞增多，并导致肠粘膜组织损伤。由于持续的GALT炎症而释放的因子诱导具有特定表型、表达谱和高NETase能力的激活的中性粒细胞群体的系统性招募。第二个主要假设是，HIV-1感染与表现抗炎表型的库普弗细胞(KCs)的频率显著降低以及向单核细胞来源的促炎KCs的显著转变有关。这种状态不会随着技术的发展而逆转，可能是由于自我更新的组织驻留的KC前体细胞耗尽所致。激活的中性粒细胞与枯否细胞和血小板相互作用，并在肝脏微血管中发生网状反应。在HIV-1感染过程中，这种机制导致慢性肝脏炎症、门脉高压、肝星状细胞激活，并导致非酒精性脂肪性肝炎(NASH)和肝纤维化的进展。因此，我们认为，对初级和次级粘膜防火墙中的先天免疫群体的两次同时攻击，即GALT和肝脏，推动了HIV-1/AIDS的疾病进展。我们建议确定在接受抗逆转录病毒治疗的HIV-1感染者中，GALT和肝脏中的中性粒细胞激活和先天免疫失调对LD进展的影响。重要的是，由于中性粒细胞群体的功能失调和中性粒细胞-巨噬细胞的相互作用可以作为药理学的靶点，了解其潜在的致病机制将导致针对HIV-1感染和其他慢性炎症性疾病的新的治疗方法。

 DESCRIPTION (provided by applicant): Liver disease (LD) has risen as a major cause of morbidity and mortality in antiretroviral therapy (ART)-treated HIV-1-infected individuals. A growing body of evidence suggests that HIV-1 alters and accelerates the pathologic processes driving LD via systemic inflammation; however, the role of neutrophils and innate immune dysregulation in these processes has not been evaluated. This application proposes that innate immune dysregulation mediated by changes in macrophage and neutrophil populations in gut- associated lymphoid tissue (GALT) and liver plays a fundamental role in HIV-1 disease progression. Neutrophils, the most abundant immune cell population in the body, are specifically geared for a sensitive detection of invading microbial and viral pathogens. GALT epithelial damage in both HIV-1 and SIV infections is temporally and spatially associated with a significant accumulation of neutrophils that directly contribute to mucosal damage. IL-17 serves as a master regulator of neutrophil function and, in conjunction with IL-10, it is required for an induction of anti-inflammatory macrophages that clear apoptotic neutrophilic infiltrates via efferocytosis and promote healing and resolution of local and systemic inflammation. The first underlying hypothesis of this proposal is that the depletion of IL-17-producing cells in the GALT of HIV-1-infected individuals blocks the induction of anti-inflammatory efferocytic tissue macrophages and causes polarization towards pro-inflammatory phenotype. This results in an accumulation of activated neutrophils that undergo NETosis and drive tissue damage in intestinal mucosa. Factors released as a result of ongoing GALT inflammation induce systemic recruitment of a population of activated neutrophils with specific phenotype, expression profile, and high capacity for NETosis. The second principal hypothesis is that HIV-1 infection is associated with a significantly decreased frequency of Kupffer cells (KCs) exhibiting anti-inflammatory phenotype and a significant shift towards blood monocyte-derived proinflammatory KCs. This state is not reversed following ART, possibly due to the depletion of self-renewing tissue-resident KC progenitors. Activated neutrophils interact with Kupffer cells and platelet and undergo NETosis in liver microvasculature. In the course of HIV-1 infection, this mechanism causes chronic liver inflammation, portal hypertension, activation of hepatic stellate cells, and results in a progression to non-alcoholic steatohepatitis (NASH) and liver fibrosis. Thus, we propose that two simultaneous hits to innate immune populations in primary and secondary mucosal firewalls, the GALT and the liver, drive disease progression in HIV-1/AIDS. We propose to determine the effect of neutrophil activation and innate immune dysregulation in GALT and liver on the progression of LD in ART- treated HIV-1-infected individuals. Importantly, since functional dysregulation of neutrophil population and neutrophil-macrophage interaction can be pharmacologically targeted, understanding of the underlying pathogenic mechanisms will lead to novel treatment approaches in HIV-1 infection and other chronic inflammatory conditions.