title: Cell rigidity and shape override CD47's "self"-signaling in phagocytosis by hyperactivating myosin-II.
abstract: A macrophage engulfs another cell or foreign particle in an adhesive process that often activates myosin-II, unless the macrophage also engages "marker of self" CD47 that inhibits myosin. For many cell types, adhesion-induced activation of myosin-II is maximized by adhesion to a rigid rather than a flexible substrate. Here we demonstrate that rigidity of a phagocytosed cell also hyperactivates myosin-II, which locally overwhelms self-signaling at a phagocytic synapse. Cell stiffness is one among many factors including shape that changes in erythropoiesis, in senescence and in diseases ranging from inherited anemias and malaria to cancer. Controlled stiffening of normal human red blood cells (RBCs) in different shapes does not compromise CD47's interaction with the macrophage self-recognition receptor signal regulatory protein alpha (SIRPA). Uptake of antibody-opsonized RBCs is always fastest with rigid RBC discocytes, which also show that maximal active myosin-II at the synapse can dominate self-signaling by CD47. Rigid but rounded RBC stomatocytes signal self better than rigid RBC discocytes, highlighting the effects of shape on CD47 inhibition. Physical properties of phagocytic targets thus regulate self signaling, as is relevant to erythropoiesis, to clearance of rigid RBCs after blood storage, clearance of rigid pathological cells such as thalassemic or sickle cells, and even to interactions of soft/stiff cancer cells with macrophages.
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA; and.
authors.forename: Nisha G
authors.identifier: http://orcid.org/0000-0002-5903-5916
authors.initials: NG
authors.lastname: Sosale
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.
authors.forename: Tahereh
authors.initials: T
authors.lastname: Rouhiparkouhi
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA; and.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bradshaw
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.
authors.forename: Rumiana
authors.initials: R
authors.lastname: Dimova
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Lipowsky
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA; and.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism*; D051928:CD47 Antigen / Q000378:metabolism*; D002450:Cell Communication; D048430:Cell Shape; D002478:Cells, Cultured; D004912:Erythrocytes / Q000166:cytology* / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology*; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D000943:Antigens, Differentiation; D051928:CD47 Antigen; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D024507:Nonmuscle Myosin Type IIA