Lebegge Els, Kancheva Daliya, Van Craenenbroeck Jolien, Ernst Sam, Bardet Pauline M R, Caro Aarushi A, Kiss Máté, Jumapili Neema Ahishakiye, Barthelmess Romina Mora, Zivalj Maida, Assaf Naela, Ali Leen, Elkrim Yvon, Demuytere Jesse, De Jonge Jan, Raes Geert, Hadadi Eva, Devoogdt Nick, Vincke Cécile, Mohavedi Kiavash, Vereecke Lars, Ceelen Wim, Stijlemans Benoit, Laoui Damya, Arnouk Sana M, Van Ginderachter Jo A
Laboratory of Cellular and Molecular Immunology, Brussels Center for Immunology (BCIM), Vrije Universiteit Brussel, Brussels, Belgium.
Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium.
Eur J Immunol. 2025 May;55(5):e202551804. doi: 10.1002/eji.202551804.
Large peritoneal macrophages (LPMs) play a role as gatekeepers of peritoneal homeostasis by providing a first line of defense against pathogens. A third of the LPMs express the surface receptor VSIG4, but it is unclear whether these cells differ from their VSIG4-negative counterparts and perform dedicated functions. We demonstrate that VSIG4, but not VSIG4, LPMs are in the majority derived from embryonal precursors, and their occurrence is largely independent of sex and microbiota but increases with age. Although their transcriptome and surface proteome are indistinguishable from VSIG4 LPMs at steady-state, VSIG4 LPMs are superior in phagocytosing S. aureus bioparticles and colorectal carcinoma (CRC) cells. Anti-VSIG4 nanobody constructs that are ADCC-enabled allowed a selective elimination of the VSIG4 LPM subset without affecting overall LPM abundance. This strategy uncovered a role for VSIG4 LPMs in lowering the first peak of parasitemia in a Trypanosoma brucei brucei infection model and in reducing CRC outgrowth in the peritoneal cavity, a prime metastatic site in CRC patients. Altogether, our data uncover a protective role for VSIG4 LPMs in infectious and oncological diseases in the peritoneal cavity.
大型腹膜巨噬细胞（LPMs）通过提供抵御病原体的第一道防线，在腹膜内环境稳定中充当守门人的角色。三分之一的LPMs表达表面受体VSIG4，但尚不清楚这些细胞是否与其VSIG4阴性的对应细胞不同并执行特定功能。我们证明，VSIG4阳性而非阴性的LPMs大多源自胚胎前体细胞，它们的出现很大程度上独立于性别和微生物群，但会随着年龄增长而增加。尽管它们的转录组和表面蛋白质组在稳态下与VSIG4阴性LPMs无法区分，但VSIG4阳性LPMs在吞噬金黄色葡萄球菌生物颗粒和结肠直肠癌（CRC）细胞方面更具优势。具有抗体依赖的细胞介导的细胞毒性（ADCC）功能的抗VSIG4纳米抗体构建体能够选择性清除VSIG4阳性LPM亚群，而不影响整体LPM丰度。这一策略揭示了VSIG4阳性LPMs在布氏布氏锥虫感染模型中降低寄生虫血症的第一个峰值以及在减少CRC在腹膜腔（CRC患者的主要转移部位）中的生长方面所起的作用。总之，我们的数据揭示了VSIG4阳性LPMs在腹膜腔感染性疾病和肿瘤性疾病中的保护作用。
