Targeting Siglecs with a sialic acid-decorated nanoparticle abrogates inflammation.
Sepsis is the most frequent cause of death in hospitalized patients, and severe sepsis is a leading contributory factor to acute respiratory distress syndrome (ARDS). At present, there is no effective treatment for these conditions, and care is primarily supportive. Murine sialic acid-binding immunoglobulin-like lectin-E (Siglec-E) and its human orthologs Siglec-7 and Siglec-9 are immunomodulatory receptors found predominantly on hematopoietic cells. These receptors are important negative regulators of acute inflammatory responses and are potential targets for the treatment of sepsis and ARDS. We describe a Siglec-targeting platform consisting of poly(lactic-co-glycolic acid) nanoparticles decorated with a natural Siglec ligand, di(α2→8) N-acetylneuraminic acid (α2,8 NANA-NP). This nanoparticle induced enhanced oligomerization of the murine Siglec-E receptor on the surface of macrophages, unlike the free α2,8 NANA ligand. Furthermore, treatment of murine macrophages with these nanoparticles blocked the production of lipopolysaccharide-induced inflammatory cytokines in a Siglec-E-dependent manner. The nanoparticles were also therapeutically beneficial in vivo in both systemic and pulmonary murine models replicating inflammatory features of sepsis and ARDS. Moreover, we confirmed the anti-inflammatory effect of these nanoparticles on human monocytes and macrophages in vitro and in a human ex vivo lung perfusion (EVLP) model of lung injury. We also established that interleukin-10 (IL-10) induced Siglec-E expression and α2,8 NANA-NP further augmented the expression of IL-10. Indeed, the effectiveness of the nanoparticle depended on IL-10. Collectively, these results demonstrated a therapeutic effect of targeting Siglec receptors with a nanoparticle-based platform under inflammatory conditions.
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
Shaun
S
Spence
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
Michelle K
MK
Greene
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK. Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
François
F
Fay
Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
Emily
E
Hams
Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
Sean P
SP
Saunders
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
Umar
U
Hamid
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
Marianne
M
Fitzgerald
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
Jonathan
J
Beck
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
Baljinder K
BK
Bains
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
Peter
P
Smyth
School of Chemistry and Chemical Engineering, Queen's University Belfast, Belfast BT9 5AG, UK.
Efrosyni
E
Themistou
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
Donna M
DM
Small
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
Daniela
D
Schmid
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
Cecilia M
CM
O'Kane
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
Denise C
DC
Fitzgerald
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK. Faculty of Pharmacy, University of Jordan, Amman 11942, Jordan.
Sharif M
SM
Abdelghany
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK. Inflammation Research, Amgen Inc., Thousand Oaks, CA 91320, USA.
James A
JA
Johnston
Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin 2, Ireland. National Children's Research Centre, Our Lady's Children's Hospital, Dublin 12, Ireland.
Padraic G
PG
Fallon
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
James F
JF
Burrows
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
Daniel F
DF
McAuley
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
Adrien
A
Kissenpfennig
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK. c.scott@qub.ac.uk.
Christopher J
CJ
Scott
D000818:Animals; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D016753:Interleukin-10 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019158:N-Acetylneuraminic Acid / Q000737:chemistry*; D053758:Nanoparticles; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation
D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D016753:Interleukin-10; D019158:N-Acetylneuraminic Acid