Aberrant interleukin-1 signalling does not increase susceptibility of mice to NOD2-dependent uveitis

Ellen Lee, Jordan J. Allensworth, Jenna S. Clowers, Holly Rosenzweig

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: NOD2 is the genetic cause of Blau syndrome, an autoinflammatory disease that manifests as coincident uveitis and arthritis. Since dysregulation of IL-1 signalling is considered a pathogenic mechanism in a number of related autoinflammatory conditions, we examined the extent to which unimpeded interleukin (IL)-1 signalling influences NOD2-dependent inflammation of the eye versus the joint. Methods: Mice deficient for IL-1R antagonist (IL-1Ra) were administered the NOD2 agonist muramyl dipeptide (MDP) by systemic (intraperitoneal) or local (intraocular and/or intra-articular) injections. NOD2-deficient mice received an intraocular injection of recombinant IL-1β. Uveitis was evaluated by intravital videomicroscopy and histopathology, and arthritis was assessed by near-infrared imaging and histopathology. Ocular levels of IL-1α, IL-1β and IL-1Ra were quantified by enzyme-linked immunosorbent assay. Results: IL-1Ra deficiency did not render mice more responsive to systemic exposure of MDP. Despite the increased production of IL-1R agonists IL-1α and IL-1β in response to intraocular injection of MDP, deficiency in IL-1Ra did not predispose mice to MDP-triggered uveitis, albeit intravascular cell rolling and adherence were exacerbated. NOD2 expression was dispensable for the potential of IL-1 to elicit uveitis. However, we find that IL-1Ra does play an important protective role in arthritis induced locally by MDP injection in the joint. Conclusions: Our findings highlight the complexity of NOD2 activation and IL-1 signalling effects that can be compounded by local environmental factors of the target organ. These observations may impact how we understand the molecular mechanisms by which NOD2 influences inflammation of the eye versus joint, and consequently, treatment options for uveitis versus arthritis.

Original languageEnglish (US)
Pages (from-to)349-357
Number of pages9
JournalClinical and Experimental Ophthalmology
Volume43
Issue number4
DOIs
StatePublished - May 1 2015

Fingerprint

Uveitis
Interleukin-1
Acetylmuramyl-Alanyl-Isoglutamine
Interleukins
Arthritis
Intraocular Injections
Joints
Inflammation
Intra-Articular Injections
Video Microscopy
Enzyme-Linked Immunosorbent Assay
Injections

Keywords

  • Arthritis
  • IL-1Ra
  • IL-1β
  • NOD2
  • Uveitis

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Aberrant interleukin-1 signalling does not increase susceptibility of mice to NOD2-dependent uveitis. / Lee, Ellen; Allensworth, Jordan J.; Clowers, Jenna S.; Rosenzweig, Holly.

In: Clinical and Experimental Ophthalmology, Vol. 43, No. 4, 01.05.2015, p. 349-357.

Research output: Contribution to journalArticle

@article{61900a926fc34d55812b6ad4f1084e90,
title = "Aberrant interleukin-1 signalling does not increase susceptibility of mice to NOD2-dependent uveitis",
abstract = "Background: NOD2 is the genetic cause of Blau syndrome, an autoinflammatory disease that manifests as coincident uveitis and arthritis. Since dysregulation of IL-1 signalling is considered a pathogenic mechanism in a number of related autoinflammatory conditions, we examined the extent to which unimpeded interleukin (IL)-1 signalling influences NOD2-dependent inflammation of the eye versus the joint. Methods: Mice deficient for IL-1R antagonist (IL-1Ra) were administered the NOD2 agonist muramyl dipeptide (MDP) by systemic (intraperitoneal) or local (intraocular and/or intra-articular) injections. NOD2-deficient mice received an intraocular injection of recombinant IL-1β. Uveitis was evaluated by intravital videomicroscopy and histopathology, and arthritis was assessed by near-infrared imaging and histopathology. Ocular levels of IL-1α, IL-1β and IL-1Ra were quantified by enzyme-linked immunosorbent assay. Results: IL-1Ra deficiency did not render mice more responsive to systemic exposure of MDP. Despite the increased production of IL-1R agonists IL-1α and IL-1β in response to intraocular injection of MDP, deficiency in IL-1Ra did not predispose mice to MDP-triggered uveitis, albeit intravascular cell rolling and adherence were exacerbated. NOD2 expression was dispensable for the potential of IL-1 to elicit uveitis. However, we find that IL-1Ra does play an important protective role in arthritis induced locally by MDP injection in the joint. Conclusions: Our findings highlight the complexity of NOD2 activation and IL-1 signalling effects that can be compounded by local environmental factors of the target organ. These observations may impact how we understand the molecular mechanisms by which NOD2 influences inflammation of the eye versus joint, and consequently, treatment options for uveitis versus arthritis.",
keywords = "Arthritis, IL-1Ra, IL-1β, NOD2, Uveitis",
author = "Ellen Lee and Allensworth, {Jordan J.} and Clowers, {Jenna S.} and Holly Rosenzweig",
year = "2015",
month = "5",
day = "1",
doi = "10.1111/ceo.12438",
language = "English (US)",
volume = "43",
pages = "349--357",
journal = "Clinical and Experimental Ophthalmology",
issn = "1442-6404",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Aberrant interleukin-1 signalling does not increase susceptibility of mice to NOD2-dependent uveitis

AU - Lee, Ellen

AU - Allensworth, Jordan J.

AU - Clowers, Jenna S.

AU - Rosenzweig, Holly

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Background: NOD2 is the genetic cause of Blau syndrome, an autoinflammatory disease that manifests as coincident uveitis and arthritis. Since dysregulation of IL-1 signalling is considered a pathogenic mechanism in a number of related autoinflammatory conditions, we examined the extent to which unimpeded interleukin (IL)-1 signalling influences NOD2-dependent inflammation of the eye versus the joint. Methods: Mice deficient for IL-1R antagonist (IL-1Ra) were administered the NOD2 agonist muramyl dipeptide (MDP) by systemic (intraperitoneal) or local (intraocular and/or intra-articular) injections. NOD2-deficient mice received an intraocular injection of recombinant IL-1β. Uveitis was evaluated by intravital videomicroscopy and histopathology, and arthritis was assessed by near-infrared imaging and histopathology. Ocular levels of IL-1α, IL-1β and IL-1Ra were quantified by enzyme-linked immunosorbent assay. Results: IL-1Ra deficiency did not render mice more responsive to systemic exposure of MDP. Despite the increased production of IL-1R agonists IL-1α and IL-1β in response to intraocular injection of MDP, deficiency in IL-1Ra did not predispose mice to MDP-triggered uveitis, albeit intravascular cell rolling and adherence were exacerbated. NOD2 expression was dispensable for the potential of IL-1 to elicit uveitis. However, we find that IL-1Ra does play an important protective role in arthritis induced locally by MDP injection in the joint. Conclusions: Our findings highlight the complexity of NOD2 activation and IL-1 signalling effects that can be compounded by local environmental factors of the target organ. These observations may impact how we understand the molecular mechanisms by which NOD2 influences inflammation of the eye versus joint, and consequently, treatment options for uveitis versus arthritis.

AB - Background: NOD2 is the genetic cause of Blau syndrome, an autoinflammatory disease that manifests as coincident uveitis and arthritis. Since dysregulation of IL-1 signalling is considered a pathogenic mechanism in a number of related autoinflammatory conditions, we examined the extent to which unimpeded interleukin (IL)-1 signalling influences NOD2-dependent inflammation of the eye versus the joint. Methods: Mice deficient for IL-1R antagonist (IL-1Ra) were administered the NOD2 agonist muramyl dipeptide (MDP) by systemic (intraperitoneal) or local (intraocular and/or intra-articular) injections. NOD2-deficient mice received an intraocular injection of recombinant IL-1β. Uveitis was evaluated by intravital videomicroscopy and histopathology, and arthritis was assessed by near-infrared imaging and histopathology. Ocular levels of IL-1α, IL-1β and IL-1Ra were quantified by enzyme-linked immunosorbent assay. Results: IL-1Ra deficiency did not render mice more responsive to systemic exposure of MDP. Despite the increased production of IL-1R agonists IL-1α and IL-1β in response to intraocular injection of MDP, deficiency in IL-1Ra did not predispose mice to MDP-triggered uveitis, albeit intravascular cell rolling and adherence were exacerbated. NOD2 expression was dispensable for the potential of IL-1 to elicit uveitis. However, we find that IL-1Ra does play an important protective role in arthritis induced locally by MDP injection in the joint. Conclusions: Our findings highlight the complexity of NOD2 activation and IL-1 signalling effects that can be compounded by local environmental factors of the target organ. These observations may impact how we understand the molecular mechanisms by which NOD2 influences inflammation of the eye versus joint, and consequently, treatment options for uveitis versus arthritis.

KW - Arthritis

KW - IL-1Ra

KW - IL-1β

KW - NOD2

KW - Uveitis

UR - http://www.scopus.com/inward/record.url?scp=84932122755&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84932122755&partnerID=8YFLogxK

U2 - 10.1111/ceo.12438

DO - 10.1111/ceo.12438

M3 - Article

C2 - 25255917

AN - SCOPUS:84932122755

VL - 43

SP - 349

EP - 357

JO - Clinical and Experimental Ophthalmology

JF - Clinical and Experimental Ophthalmology

SN - 1442-6404

IS - 4

ER -