title: Neutrophil recruitment limited by high-affinity bent β2 integrin binding ligand in cis.
abstract: Neutrophils are essential for innate immunity and inflammation and many neutrophil functions are β2 integrin-dependent. Integrins can extend (E(+)) and acquire a high-affinity conformation with an 'open' headpiece (H(+)). The canonical switchblade model of integrin activation proposes that the E(+) conformation precedes H(+), and the two are believed to be structurally linked. Here we show, using high-resolution quantitative dynamic footprinting (qDF) microscopy combined with a homogenous conformation-reporter binding assay in a microfluidic device, that a substantial fraction of β2 integrins on human neutrophils acquire an unexpected E(-)H(+) conformation. E(-)H(+) β2 integrins bind intercellular adhesion molecules (ICAMs) in cis, which inhibits leukocyte adhesion in vitro and in vivo. This endogenous anti-inflammatory mechanism inhibits neutrophil aggregation, accumulation and inflammation.
authors: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, California 92037, USA.
authors: Zhichao
authors: 0000-0001-5385-9626
authors: Z
authors: Fan
authors: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, California 92037, USA.|Department of Bioengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors: Sara
authors: S
authors: McArdle
authors: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, California 92037, USA.
authors: Alex
authors: A
authors: Marki
authors: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, California 92037, USA.
authors: Zbigniew
authors: Z
authors: Mikulski
authors: Department of Physics, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors: Edgar
authors: E
authors: Gutierrez
authors: Theodor Kocher Institute, University of Bern, 1 Freiestrasse, 3012 Bern, Switzerland.
authors: Britta
authors: B
authors: Engelhardt
authors: Theodor Kocher Institute, University of Bern, 1 Freiestrasse, 3012 Bern, Switzerland.
authors: Urban
authors: U
authors: Deutsch
authors: Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors: Mark
authors: 0000-0002-5685-5417
authors: M
authors: Ginsberg
authors: Department of Physics, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors: Alex
authors: A
authors: Groisman
authors: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, California 92037, USA.|Department of Bioengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors: Klaus
authors: K
authors: Ley
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D018821:CD18 Antigens / Q000737:chemistry / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D021621:Imaging, Three-Dimensional; D007249:Inflammation / Q000097:blood / Q000276:immunology*; D000069416:Intravital Microscopy / Q000379:methods; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057054:Molecular Imaging / Q000379:methods; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D018183:Transplantation Chimera
chemical_list: D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D008024:Ligands; D011994:Recombinant Proteins