Maisonneuve Charles, Tsang Derek K L, Foerster Elisabeth G, Robert Lukian Maxence, Mukherjee Tapas, Prescott Dave, Tattoli Ivan, Lemire Paul, Winer Daniel A, Winer Shawn, Streutker Catherine J, Geddes Kaoru, Cadwell Ken, Ferrero Richard L, Martin Alberto, Girardin Stephen E, Philpott Dana J
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Cell Rep. 2021 Jan 26;34(4):108677. doi: 10.1016/j.celrep.2020.108677.
Pioneering studies from the early 1980s suggested that bacterial peptidoglycan-derived muramyl peptides (MPs) could exert either stimulatory or immunosuppressive functions depending, in part, on chronicity of exposure. However, this Janus-faced property of MPs remains largely unexplored. Here, we demonstrate the immunosuppressive potential of Nod1, the bacterial sensor of diaminopimelic acid (DAP)-containing MPs. Using a model of self-limiting peritonitis, we show that systemic Nod1 activation promotes an autophagy-dependent reprogramming of macrophages toward an alternative phenotype. Moreover, Nod1 stimulation induces the expansion of myeloid-derived suppressor cells (MDSCs) and maintains their immunosuppressive potential via arginase-1 activity. Supporting the role of MDSCs and tumor-associated macrophages in cancer, we demonstrate that myeloid-intrinsic Nod1 expression sustains intra-tumoral arginase-1 levels to foster an immunosuppressive and tumor-permissive microenvironment during colorectal cancer (CRC) development. Our findings support the notion that bacterial products, via Nod1 detection, modulate the immunosuppressive activity of myeloid cells and fuel tumor progression in CRC.
20世纪80年代早期的开创性研究表明，细菌肽聚糖衍生的胞壁酰肽（MPs）可发挥刺激或免疫抑制功能，这部分取决于暴露的持续性。然而，MPs这种双面性的特性在很大程度上仍未得到探索。在此，我们证明了含二氨基庚二酸（DAP）的MPs的细菌传感器Nod1具有免疫抑制潜力。使用自限性腹膜炎模型，我们发现全身Nod1激活促进巨噬细胞自噬依赖性重编程为另一种表型。此外，Nod1刺激诱导髓源性抑制细胞（MDSCs）扩增，并通过精氨酸酶-1活性维持其免疫抑制潜力。为支持MDSCs和肿瘤相关巨噬细胞在癌症中的作用，我们证明髓系特异性Nod1表达维持肿瘤内精氨酸酶-1水平，以在结直肠癌（CRC）发展过程中促进免疫抑制和肿瘤允许性微环境。我们的研究结果支持这样一种观点，即细菌产物通过Nod1检测调节髓系细胞的免疫抑制活性，并推动CRC中的肿瘤进展。
