TY - JOUR
T1 - Tamm-Horsfall glycoprotein engages human Siglec-9 to modulate neutrophil activation in the urinary tract
AU - Patras, Kathryn A.
AU - Coady, Alison
AU - Olson, Joshua
AU - Ali, Syed Raza
AU - Ramachandrarao, Satish P.
AU - Kumar, Satish
AU - Varki, Ajit
AU - Nizet, Victor
N1 - Funding Information:
We thank Michael Florio for breeding and maintaining the mice along with the UCSD vivarium staff. Studies were supported by NIH/NHLBI Program of Excellence in Glycosciences (P01 HL107150 to VN and AV) and by NIH/NHLBI grant HL125352 (to VN). KAP was supported through a postdoctoral fellowship from University of California Chancellor’s Postdoctoral Fellowship Program and AC through a postdoctoral fellowship from the AP Giannini Foundation. We are grateful to Ross Corriden for assistance with neutrophil studies.
Publisher Copyright:
© 2017 Australasian Society for Immunology Inc. All rights reserved.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Urinary tract infections are a major problem in human medicine for which better understanding of native immune defenses may reveal new pathways for therapeutic intervention. Tamm-Horsfall glycoprotein (THP), the most abundant urinary protein, interacts with bacteria including uropathogenic Escherichia coli (UPEC) as well host immune cells. In addition to its well-studied functions to antagonize bacterial colonization, we hypothesize that THP serves a critical host defense function through innate immune modulation. Using isolated human neutrophils, we found that THP binds neutrophils and that this interaction reduces reactive oxygen species generation, chemotaxis and killing of UPEC. We discovered that THP engages the inhibitory neutrophil receptor sialic acid-binding Ig-like lectin-9 (Siglec-9), and mouse functional ortholog Siglec-E, in a manner dependent on sialic acid on its N-glycan moieties. THP-null mice have significantly more neutrophils present in the urine compared with wild-type mice, both with and without the presence of inflammatory stimuli. These data support THP as an important negative regulator of neutrophil activation in the urinary tract, with dual functions to counteract bacterial colonization and suppress excessive inflammation within the urinary tract.
AB - Urinary tract infections are a major problem in human medicine for which better understanding of native immune defenses may reveal new pathways for therapeutic intervention. Tamm-Horsfall glycoprotein (THP), the most abundant urinary protein, interacts with bacteria including uropathogenic Escherichia coli (UPEC) as well host immune cells. In addition to its well-studied functions to antagonize bacterial colonization, we hypothesize that THP serves a critical host defense function through innate immune modulation. Using isolated human neutrophils, we found that THP binds neutrophils and that this interaction reduces reactive oxygen species generation, chemotaxis and killing of UPEC. We discovered that THP engages the inhibitory neutrophil receptor sialic acid-binding Ig-like lectin-9 (Siglec-9), and mouse functional ortholog Siglec-E, in a manner dependent on sialic acid on its N-glycan moieties. THP-null mice have significantly more neutrophils present in the urine compared with wild-type mice, both with and without the presence of inflammatory stimuli. These data support THP as an important negative regulator of neutrophil activation in the urinary tract, with dual functions to counteract bacterial colonization and suppress excessive inflammation within the urinary tract.
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U2 - 10.1038/icb.2017.63
DO - 10.1038/icb.2017.63
M3 - Article
C2 - 28829050
AN - SCOPUS:85034592032
SN - 0818-9641
VL - 95
SP - 960
EP - 965
JO - Immunology and Cell Biology
JF - Immunology and Cell Biology
IS - 10
ER -