肺组织细胞对肺泡巨噬细胞固有免疫记忆的塑造及其机制研究

Pneumonia is a common and severe disease worldwide. Alveolar macrophages (AM) are the first line of cellular defense in airspaces. When macrophages are exposed to pathogen-associated molecular pattern (PAMP), such as Gram-negative bacterial lipopolysaccharide (LPS), they are reprogrammed and they usually become hypo-responsive to subsequent challenges (tolerant). Distinct from macrophages from other sites, after exposure to LPS in vivo, AM do not develop tolerance. However, the underlying mechanisms and its effects on lung defense against infections are not clear. Our preliminary experiments show that, intranasally instilled low-dose LPS induced augmented IL-6 and MCP-1 responses to a second dose of LPS challenge in AM and AM had increased phagocytic activities, suggesting that innate immune memory was generated (primed). The LPS-instilled mice became more resistant to lung infections than naïve mice. Furthermore, alveolar epithelial cells promoted the immune responses and the innate immune memory of AM. By using immunological, biochemical, and molecular biological techniques, we propose to study how alveolar epithelial cells motivate AM and shape the innate immune memory in AM and how primed AM contribute to enhanced lung anti-microbial immunity. This work may open new avenue toward developing pneumonia vaccine against unpredictable or a broad-spectrum of pathogens.

感染性肺炎困扰人类。肺泡巨噬细胞(Alveolar Macrophages, AM)在肺免疫防御中发挥重要作用。通常巨噬细胞受病原相关分子模式如革兰氏阴性菌脂多糖(LPS)刺激后，程序重编，对再刺激应答减弱（耐受）。与其它部位巨噬细胞不同，在体暴露于LPS后，AM不产生耐受，但其机制不明，对肺免疫防御的影响未知。我们的前期实验结果表明，经鼻滴注小剂量LPS后，小鼠AM 对LPS再刺激诱导的IL-6、MCP-1等应答增强，AM吞菌能力提高，表明AM产生固有免疫记忆（致敏）；小鼠抗肺部感染能力增强；而肺泡上皮细胞促进AM致敏。在本项目中，我们将利用免疫学、生物化学和分子生物学等手段，从PAMP分子-肺组织细胞-AM-肺区域免疫这个新视角深入研究受到病原体入侵后，肺泡上皮细胞如何协同动员AM，并促进AM产生固有免疫记忆，增强肺免疫防御功能，本课题将为预防未知或广谱病原体所致肺炎开拓新思路。

肺泡巨噬细胞位于肺泡腔内，为肺免疫防御的第一线。不同于其它部位的巨噬细胞，在体暴露于LPS后，肺泡巨噬细胞不产生内毒素耐受，提示其所处的肺组织微环境调控其重编程。肺泡巨噬细胞与肺泡上皮细胞密切接触且进行信息交流，但至今，肺泡上皮细胞能否调控肺泡巨噬细胞的固有免疫应答并不明确。我们发现经鼻滴注LPS后，肺泡巨噬细胞增强其对多种TLR刺激物的应答；体外实验表明，LPS刺激后，肺泡上皮细胞促进肺泡巨噬细胞的固有免疫应答并减轻内毒素耐受的发生；在体暴露于LPS后，肺泡巨噬细胞吞菌和杀菌能力增强，且抵抗肺部革兰氏阴性菌感染的能力也增强。此项研究阐明了肺泡上皮细胞增强肺泡巨噬细胞的固有免疫应答及重塑巨噬细胞而促进肺免疫防御功能，为增强肺对抗多种病原体的入侵提供新思路。