A common genetic variant in TLR1 enhances human neutrophil priming and impacts length of intensive care stay in pediatric sepsis

Laura C. Whitmore, Jessica S. Hook, Amanda R. Philiph, Brieanna M. Hilkin, Xinyu Bing, Chul Ahn, Hector R. Wong, Polly J. Ferguson, Jessica G. Moreland

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Polymorphonuclear leukocytes (PMN) achieve an intermediate or primed state of activation following stimulation with certain agonists. Primed PMN have enhanced responsiveness to subsequent stimuli, which can be beneficial in eliminating microbes but may cause host tissue damage in certain disease contexts, including sepsis. As PMN priming by TLR4 agonists is well described, we hypothesized that ligation of TLR2/1 or TLR2/6 would prime PMN. Surprisingly,PMNfrom only a subset of donors were primed in response to the TLR2/1 agonist, Pam3CSK4, although PMN from all donors were primed by the TLR2/6 agonist, FSL-1. Priming responses included generation of intracellular and extracellular reactive oxygen species, MAPK phosphorylation, integrin activation, secondary granule exocytosis, and cytokine secretion. Genotyping studies revealed that PMN responsiveness to Pam3CSK4 was enhanced by a common single-nucleotide polymorphism (SNP) in TLR1 (rs5743618). Notably, PMN from donors with the SNP had higher surface levels of TLR1 and were demonstrated to have enhanced association of TLR1 with the endoplasmic reticulum chaperone gp96. We analyzed TLR1 genotypes in a pediatric sepsis database and found that patients with sepsis or septic shock who had a positive blood culture and were homozygous for the SNP associated with neutrophil priming had prolonged pediatric intensive care unit length of stay. We conclude that this TLR1 SNP leads to excessive PMN priming in response to cell stimulation. Based on our finding that septic children with this SNP had longer pediatric intensive care unit stays, we speculate that this SNP results in hyperinflammation in diseases such as sepsis.

Original languageEnglish (US)
Pages (from-to)1376-1386
Number of pages11
JournalJournal of Immunology
Volume196
Issue number3
DOIs
StatePublished - Feb 1 2016

Fingerprint

Critical Care
Sepsis
Neutrophils
Pediatrics
Single Nucleotide Polymorphism
Pediatric Intensive Care Units
Tissue Donors
Exocytosis
Septic Shock
Integrins
Endoplasmic Reticulum
Ligation
Reactive Oxygen Species
Length of Stay
Genotype
Phosphorylation
Databases
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

A common genetic variant in TLR1 enhances human neutrophil priming and impacts length of intensive care stay in pediatric sepsis. / Whitmore, Laura C.; Hook, Jessica S.; Philiph, Amanda R.; Hilkin, Brieanna M.; Bing, Xinyu; Ahn, Chul; Wong, Hector R.; Ferguson, Polly J.; Moreland, Jessica G.

In: Journal of Immunology, Vol. 196, No. 3, 01.02.2016, p. 1376-1386.

Research output: Contribution to journalArticle

Whitmore, Laura C. ; Hook, Jessica S. ; Philiph, Amanda R. ; Hilkin, Brieanna M. ; Bing, Xinyu ; Ahn, Chul ; Wong, Hector R. ; Ferguson, Polly J. ; Moreland, Jessica G. / A common genetic variant in TLR1 enhances human neutrophil priming and impacts length of intensive care stay in pediatric sepsis. In: Journal of Immunology. 2016 ; Vol. 196, No. 3. pp. 1376-1386.
@article{051a2dac94e540a0be94716e9dea4238,
title = "A common genetic variant in TLR1 enhances human neutrophil priming and impacts length of intensive care stay in pediatric sepsis",
abstract = "Polymorphonuclear leukocytes (PMN) achieve an intermediate or primed state of activation following stimulation with certain agonists. Primed PMN have enhanced responsiveness to subsequent stimuli, which can be beneficial in eliminating microbes but may cause host tissue damage in certain disease contexts, including sepsis. As PMN priming by TLR4 agonists is well described, we hypothesized that ligation of TLR2/1 or TLR2/6 would prime PMN. Surprisingly,PMNfrom only a subset of donors were primed in response to the TLR2/1 agonist, Pam3CSK4, although PMN from all donors were primed by the TLR2/6 agonist, FSL-1. Priming responses included generation of intracellular and extracellular reactive oxygen species, MAPK phosphorylation, integrin activation, secondary granule exocytosis, and cytokine secretion. Genotyping studies revealed that PMN responsiveness to Pam3CSK4 was enhanced by a common single-nucleotide polymorphism (SNP) in TLR1 (rs5743618). Notably, PMN from donors with the SNP had higher surface levels of TLR1 and were demonstrated to have enhanced association of TLR1 with the endoplasmic reticulum chaperone gp96. We analyzed TLR1 genotypes in a pediatric sepsis database and found that patients with sepsis or septic shock who had a positive blood culture and were homozygous for the SNP associated with neutrophil priming had prolonged pediatric intensive care unit length of stay. We conclude that this TLR1 SNP leads to excessive PMN priming in response to cell stimulation. Based on our finding that septic children with this SNP had longer pediatric intensive care unit stays, we speculate that this SNP results in hyperinflammation in diseases such as sepsis.",
author = "Whitmore, {Laura C.} and Hook, {Jessica S.} and Philiph, {Amanda R.} and Hilkin, {Brieanna M.} and Xinyu Bing and Chul Ahn and Wong, {Hector R.} and Ferguson, {Polly J.} and Moreland, {Jessica G.}",
year = "2016",
month = "2",
day = "1",
doi = "10.4049/jimmunol.1500856",
language = "English (US)",
volume = "196",
pages = "1376--1386",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "3",

}

TY - JOUR

T1 - A common genetic variant in TLR1 enhances human neutrophil priming and impacts length of intensive care stay in pediatric sepsis

AU - Whitmore, Laura C.

AU - Hook, Jessica S.

AU - Philiph, Amanda R.

AU - Hilkin, Brieanna M.

AU - Bing, Xinyu

AU - Ahn, Chul

AU - Wong, Hector R.

AU - Ferguson, Polly J.

AU - Moreland, Jessica G.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Polymorphonuclear leukocytes (PMN) achieve an intermediate or primed state of activation following stimulation with certain agonists. Primed PMN have enhanced responsiveness to subsequent stimuli, which can be beneficial in eliminating microbes but may cause host tissue damage in certain disease contexts, including sepsis. As PMN priming by TLR4 agonists is well described, we hypothesized that ligation of TLR2/1 or TLR2/6 would prime PMN. Surprisingly,PMNfrom only a subset of donors were primed in response to the TLR2/1 agonist, Pam3CSK4, although PMN from all donors were primed by the TLR2/6 agonist, FSL-1. Priming responses included generation of intracellular and extracellular reactive oxygen species, MAPK phosphorylation, integrin activation, secondary granule exocytosis, and cytokine secretion. Genotyping studies revealed that PMN responsiveness to Pam3CSK4 was enhanced by a common single-nucleotide polymorphism (SNP) in TLR1 (rs5743618). Notably, PMN from donors with the SNP had higher surface levels of TLR1 and were demonstrated to have enhanced association of TLR1 with the endoplasmic reticulum chaperone gp96. We analyzed TLR1 genotypes in a pediatric sepsis database and found that patients with sepsis or septic shock who had a positive blood culture and were homozygous for the SNP associated with neutrophil priming had prolonged pediatric intensive care unit length of stay. We conclude that this TLR1 SNP leads to excessive PMN priming in response to cell stimulation. Based on our finding that septic children with this SNP had longer pediatric intensive care unit stays, we speculate that this SNP results in hyperinflammation in diseases such as sepsis.

AB - Polymorphonuclear leukocytes (PMN) achieve an intermediate or primed state of activation following stimulation with certain agonists. Primed PMN have enhanced responsiveness to subsequent stimuli, which can be beneficial in eliminating microbes but may cause host tissue damage in certain disease contexts, including sepsis. As PMN priming by TLR4 agonists is well described, we hypothesized that ligation of TLR2/1 or TLR2/6 would prime PMN. Surprisingly,PMNfrom only a subset of donors were primed in response to the TLR2/1 agonist, Pam3CSK4, although PMN from all donors were primed by the TLR2/6 agonist, FSL-1. Priming responses included generation of intracellular and extracellular reactive oxygen species, MAPK phosphorylation, integrin activation, secondary granule exocytosis, and cytokine secretion. Genotyping studies revealed that PMN responsiveness to Pam3CSK4 was enhanced by a common single-nucleotide polymorphism (SNP) in TLR1 (rs5743618). Notably, PMN from donors with the SNP had higher surface levels of TLR1 and were demonstrated to have enhanced association of TLR1 with the endoplasmic reticulum chaperone gp96. We analyzed TLR1 genotypes in a pediatric sepsis database and found that patients with sepsis or septic shock who had a positive blood culture and were homozygous for the SNP associated with neutrophil priming had prolonged pediatric intensive care unit length of stay. We conclude that this TLR1 SNP leads to excessive PMN priming in response to cell stimulation. Based on our finding that septic children with this SNP had longer pediatric intensive care unit stays, we speculate that this SNP results in hyperinflammation in diseases such as sepsis.

UR - http://www.scopus.com/inward/record.url?scp=84957705651&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84957705651&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1500856

DO - 10.4049/jimmunol.1500856

M3 - Article

VL - 196

SP - 1376

EP - 1386

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 3

ER -