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Peer-reviewedCC BYNature communications

Tall adhesions overcome cell surface steric interference and rescue antibody-dependent phagocytosis in macrophages.

  • Aymeric Chorlay1
  • Aaron M Joffe1,2
  • Jared Huzar3
  • Jaffar Hasnain4
  • Caitlin E Cornell1
  • Phillip L Geissler4,5
  • Daniel A Fletcher6,7,8,9,10
10 affiliations
  1. 1Department of Bioengineering, University of California Berkeley, Berkeley, CA, USA.
  2. 2UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA, USA.
  3. 3Biophysics Graduate Group, University of California, Berkeley, Berkeley, CA, USA.
  4. 4Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
  5. 5Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  6. 6Department of Bioengineering, University of California Berkeley, Berkeley, CA, USA. [email protected].
  7. 7UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA, USA. [email protected].
  8. 8Biophysics Graduate Group, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  9. 9Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. [email protected].
  10. 10Chan Zuckerberg Biohub, San Francisco, CA, USA. [email protected].
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Abstract

Macrophages phagocytose IgG-opsonized target cells by forming phagocytic synapses upon binding of IgG to Fcγ receptors (FcγR) expressed on the macrophage surface. However, binding requires accessibility of both IgG and FcγR within densely packed glycocalyces that decorate the macrophage and target cell surfaces. Here, we use cell-like target particles to show that non-binding 'bystander' proteins not directly involved in phagocytic signaling can sterically interfere with FcγR engagement, ultimately inhibiting synapse formation and phagocytosis. Furthermore, we demonstrate that adding a tall binding protein to the target particle overcomes bystander-mediated inhibition and substantially recovers phagocytosis in a process we call kinetic enhancement. We confirm that tall binders are sufficient to drive short binder engagement in vitro and introduce theory and simulations to explain the nonmonotonic dependence of phagocytosis on tall binder surface density. These findings show that kinetic enhancement is a general and tunable feature of interface formation, providing a strategy for re-engineering transition states to promote short receptor engagement at cell-cell contacts.

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Cite

BibTeXRIS
BibTeX
@article{chorlay2026tall,
  title = {{Tall adhesions overcome cell surface steric interference and rescue antibody-dependent phagocytosis in macrophages.}},
  author = {Aymeric Chorlay and Aaron M Joffe and Jared Huzar and Jaffar Hasnain and Caitlin E Cornell and Phillip L Geissler and Daniel A Fletcher},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-78095-7},
  url = {https://europepmc.org/article/MED/42957709},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Tall adhesions overcome cell surface steric interference and rescue antibody-dependent phagocytosis in macrophages.
AU  - Aymeric Chorlay
AU  - Aaron M Joffe
AU  - Jared Huzar
AU  - Jaffar Hasnain
AU  - Caitlin E Cornell
AU  - Phillip L Geissler
AU  - Daniel A Fletcher
PY  - 2026
DA  - 2026/09/28
JO  - Nature communications
DO  - 10.1038/s41467-026-78095-7
UR  - https://europepmc.org/article/MED/42957709
AB  - Macrophages phagocytose IgG-opsonized target cells by forming phagocytic synapses upon binding of IgG to Fcγ receptors (FcγR) expressed on the macrophage surface. However, binding requires accessibility of both IgG and FcγR within densely packed glycocalyces that decorate the macrophage and target cell surfaces. Here, we use cell-like target particles to show that non-binding 'bystander' proteins not directly involved in phagocytic signaling can sterically interfere with FcγR engagement, ultimately inhibiting synapse formation and phagocytosis. Furthermore, we demonstrate that adding a tall binding protein to the target particle overcomes bystander-mediated inhibition and substantially recovers phagocytosis in a process we call kinetic enhancement. We confirm that tall binders are sufficient to drive short binder engagement in vitro and introduce theory and simulations to explain the nonmonotonic dependence of phagocytosis on tall binder surface density. These findings show that kinetic enhancement is a general and tunable feature of interface formation, providing a strategy for re-engineering transition states to promote short receptor engagement at cell-cell contacts.
SN  - 2041-1723
ER  -