{"doi":"10.1016/j.jbc.2021.100801","title":"CR3 ruffles FcγR’s claim over phagocytic cups","abstract":"Phagocytosis plays diverse roles in biology, but our understanding of the purpose, interplay, and cell signaling mechanisms associated with different modes of phagocytosis is limited, without being able to capture and visualize each step in this rapid process from the beginning to end. A new study by Walbaum et al. uses stunning time-lapse 3D imaging of the engulfment of erythrocytes by macrophages via sinking, ruffling, and cup formation, unequivocally confirming a visionary 44-year-old theory derived from still electron microscopy photos that phagocytosis mediated by complement receptor CR3 occurs via a sinking mechanism and antibody-mediated phagocytosis occurs via phagocytic cup formation. The article also challenges the dogma, showing that phagocytic cup formation is not unique to antibody receptor phagocytosis, rather CR3 plays a complex role in different modes of phagocytosis. For example, inhibition of antibody-mediated phagocytosis leads to a compensatory upregulation of CR3-mediated sinking phagocytosis. These findings animate, in vivid colors, processes previously only captured as stills, exposing interactions between different phagocytic mechanisms and altering our basic understanding of this important process. Phagocytosis plays diverse roles in biology, but our understanding of the purpose, interplay, and cell signaling mechanisms associated with different modes of phagocytosis is limited, without being able to capture and visualize each step in this rapid process from the beginning to end. A new study by Walbaum et al. uses stunning time-lapse 3D imaging of the engulfment of erythrocytes by macrophages via sinking, ruffling, and cup formation, unequivocally confirming a visionary 44-year-old theory derived from still electron microscopy photos that phagocytosis mediated by complement receptor CR3 occurs via a sinking mechanism and antibody-mediated phagocytosis occurs via phagocytic cup formation. The article also challenges the dogma, showing that phagocytic cup formation is not unique to antibody receptor phagocytosis, rather CR3 plays a complex role in different modes of phagocytosis. For example, inhibition of antibody-mediated phagocytosis leads to a compensatory upregulation of CR3-mediated sinking phagocytosis. These findings animate, in vivid colors, processes previously only captured as stills, exposing interactions between different phagocytic mechanisms and altering our basic understanding of this important process. Phagocytosis continues to intrigue researchers after 140 years, including discoveries of its roles in infectious diseases, aging, cancer, diabetes, and neurodegenerative diseases. In many diseases and in aging, RNA-Seq data show that the expression of genes regulating phagocytosis is dysregulated, including TREM2 and DAP12 in Alzheimer’s disease (AD) (1Griciuc A. Tanzi R.E. The role of innate immune genes in Alzheimer's disease.Curr. Opin. Neurol. 2021; 34: 228-236Crossref PubMed Scopus (9) Google Scholar). However, visualizing step-by-step morphological changes associated with engulfment and related mechanisms is difficult with still images from a process where critical steps last a few seconds and cells return to normal within a few minutes. Now high-resolution video in real time can help us visualize the entire process from the beginning to end, allowing us to better understand the signaling that controls steps in these pathways. Two of the most well-understood phagocytic pathways are complement-mediated phagocytosis and antibody-mediated phagocytosis. The theory proposed by Kaplan in 1977 (2Kaplan G. Differences in the mode of phagocytosis with Fc and C3 receptors in macrophages.Scand. J. Immunol. 1977; 6: 797-807Crossref PubMed Scopus (164) Google Scholar), which has stood up well to time, used elegant scanning and transmission electron microscopy to show that complement-mediated phagocytosis occurs via sinking of the cargo into the membrane, whereas antibody-mediated phagocytosis ind","journal":"Journal of Biological Chemistry","year":2021,"id":224372,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9461,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":344634,"name":"Sally A. Frautschy","orcid":"0000-0003-0194-0363","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:18.470602Z","pmid":"34019878","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}