Fountain Aaron, Mansat Mélanie, Lackraj Tracy, Gimenez Maria C, Moussaoui Serene, Ezzo Maya, Soffiaturo Sierra, Urdaneta Elijah, Verdawala Munira B, Fung Karen, Lancaster Charlene, Somerville Elliott, Hinz Boris, Terebiznik Mauricio R, Botelho Roberto J
Graduate Program in Molecular Science, Toronto Metropolitan University, Toronto, Ontario, M5B 2K3, Canada.
Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, Ontario, M5B 2K3, Canada.
J Cell Sci. 2025 Aug 15;138(16). doi: 10.1242/jcs.263539. Epub 2025 Aug 29.
During phagocytosis, a phagocytic cup grows via F-actin remodeling and localized secretion to entrap a particle within a phagosome, which then fuses with endosomes and lysosomes to digest the particle, followed by phagosome resolution. As spatially limited systems, phagocytes have a maximal phagocytic capacity, at which point further uptake must be reduced. However, the processes responsible for phagocytic appetite exhaustion as phagocytes reach their maximal phagocytic capacity are poorly defined. We found that macrophages at their capacity have lower surface levels of Fcγ receptors but overexpression of these receptors did not increase their capacity, suggesting that receptor levels are not limiting. We found that surface membrane in-folding, membrane tension and cortical F-actin were all reduced in exhausted macrophages. Although this might contribute to appetite suppression, we also found that 'free' endosomes and lysosomes were severely depleted in exhausted macrophages. Consequently, focal exocytosis at sites of externally bound particles was reduced. In comparison, macrophages recovered their appetite if phagosome resolution was permitted. We propose that depletion of the endomembrane pools is a major determinant of phagocytic fatigue as macrophages reach their phagocytic capacity.
在吞噬作用过程中，吞噬杯通过F-肌动蛋白重塑和局部分泌生长，以将颗粒捕获在吞噬体内，吞噬体随后与内体和溶酶体融合以消化颗粒，接着是吞噬体的消解。作为空间有限的系统，吞噬细胞具有最大吞噬能力，此时必须减少进一步的摄取。然而，吞噬细胞达到其最大吞噬能力时导致吞噬欲望耗尽的过程尚不清楚。我们发现处于最大吞噬能力的巨噬细胞表面Fcγ受体水平较低，但这些受体的过表达并未增加其吞噬能力，这表明受体水平并非限制因素。我们发现，耗尽的巨噬细胞中表面膜内陷、膜张力和皮质F-肌动蛋白均降低。虽然这可能有助于抑制吞噬欲望，但我们还发现，耗尽的巨噬细胞中“游离”的内体和溶酶体严重减少。因此，外部结合颗粒部位的局部胞吐作用减少。相比之下，如果允许吞噬体消解，巨噬细胞会恢复其吞噬欲望。我们提出，当巨噬细胞达到其吞噬能力时，内膜池的耗尽是吞噬疲劳的主要决定因素。
