The role of TLRs, Type II IFN and Type III IFN in a Murine Model of Autoinflammation
Project Number5R37AI155901-04
Former Number1R01AI155901-01
Contact PI/Project LeaderMARSHAK-ROTHSTEIN, ANN
Awardee OrganizationUNIV OF MASSACHUSETTS MED SCH WORCESTER
Description
Abstract Text
ABSTRACT
Common pathophysiological mechanisms are thought to promote the cutaneous and systemic manifestations
of lupus. Thus a better understanding of the factors that promote CLE are likely to provide important insights as
far as the pathogenesis of SLE. Nevertheless, it is also likely that tissue specific effector mechanisms account
for the diverse clinical presentations exhibited by SLE patient populations. Since 75% of SLE patients exhibit
skin lesions of some sort, and UV exposure of the skin is often associated with lupus flares, it is surprising that
there have been relatively few mechanistic studies that address initiation, progression and recurrence of CLE.
One reason for this gap is that murine models available for the study of CLE have been limited – despite the
numerous murine models of SLE, models that accurately reflect the central features of CLE are much more
limited. We have now develop an inducible model of lupus like skin inflammation (LLSI), initiated by T cell
transfer, that recapitulates many of the features of CLE. These include a prominent role for skin-infiltrating
IFNγ-producing Th1 cells, excessive keratinocyte death, autoantibody deposition at the dermal/epidermal
border, increased expression of CxCL9, CxCL10, CxCL11, CCL8, and accumulation of pDCs in the skin. There
are also mechanistic similarities between our LLSI model and other inducible as well as genetically
programmed murine models of SLE; they all depend on the expression of TLR7 and are exacerbated by the
absence of TLR9. Therefore our LLSI mice provide a novel, rapid and reproducible system for exploring the
effector mechanisms responsible for the induction and regulation of cutaneous lupus. This application will
focus on TLR9 and FasL. As mentioned, TLR9 negatively regulates the development of both cutaneous and
systemic lupus, but whether TLR9 works passively by simply competing with TLR7 for access to the
endosomal trafficking chaperone Unc93B1, or actively by inducing molecules dependent on a TLR9 signaling
cascade that limit inflammation, has not been addressed. We have also recently shown that the development
of skin lesions is completely dependent T cell FasL expression, but whether FasL promotes disease indirectly
by inducing cell death and creating cell debris and/or directly by inducing the production of pro-inflammatory
cytokines is unresolved. Interplay between TLR9 and FasL may be an important amplification loop in LLSI -
TLR ligands induce upregulation of Fas and FasL generates cell debris that can activate endosomal TLRs. We
propose to address the questions by using gene-targeted mice with discriminating mutations for both in vitro
and in vivo (LLSI) studies. In Aim 1, we will use mice that express normal levels of a form of TLR9 that cannot
engage MyD88, and in Aim 2, we will use mice that express a Caspase 8 mutation which removes the
Caspase 8 autocleavage site and thereby prevents FasL-induced apoptosis but not chemokine production.
Together, these studies should help identify the most effective therapeutic strategies for targeting TLR9 and
FasL pathways to prevent or ameliorate the development of cutaneous lupus.
Public Health Relevance Statement
PROJECT NARRATIVE
Mendelian disorders associated with increased IFN levels have now been grouped as a distinct disease
category. These patients develop debilitating and potentially fatal conditions where the pathogenesis is poorly
understood and therapeutic options are limited. We have identified a murine model of DNaseII deficiency that
recapitulates many of the clinical features of patients with DNaseII hypomorphic mutations, including liver
fibrosis. This application will explore the interplay between nucleic acid sensors and elevated levels of type II
and type III IFNs in the pathogenesis of DNaseII deficiency and related disorders that can lead to liver fibrosis.
The mechanisms we are exploring are highly relevant to human disease and the key to future targeted
therapies.
NIH Spending Category
No NIH Spending Category available.
Project Terms
AddressAntigen-Presenting CellsAttentionAutoantibodiesAutoimmune DiseasesB-LymphocytesBrainCASP8 geneCCL8 geneCategoriesCell DeathCell Death InductionCell LineageCellsCentral Nervous System DiseasesCessation of lifeChronicClinicalCutaneousDNADataDefectDeoxyribonucleasesDependenceDepositionDermalDevelopmentDiseaseEndosomesEnvironmentEpithelial CellsExhibitsExtramedullary HematopoiesisFibrosisFlareFlow CytometryFutureGene TargetingGoalsHepatocyteHeterogeneityImmuneIn VitroInduction of ApoptosisInfantInfiltrationInflammationInflammatoryInterferon Type IIInterferonsKnock-outKnockout MiceLigandsLiver FibrosisLupusMacrophageMemoryMendelian disorderMitochondrial RNAModelingMolecular ChaperonesMusMutationMyelogenousMyeloid Cell ActivationMyocarditisNucleic AcidsOrganPathogenesisPathogenicityPathway interactionsPatientsPattern recognition receptorPhenotypePlayProductionProteinsPulmonary FibrosisRecurrenceRegulationReproducibilityRibosomal RNARoleSerumSignal TransductionSiteSkinSortingSystemSystemic Lupus ErythematosusT-Cell ActivationT-LymphocyteTLR7 geneTestingTh1 CellsTherapeuticTissuesUV Radiation ExposureUp-RegulationWorkautoinflammationautoinflammatoryautoinflammatory diseasescytokineds-DNAexhaustiongain of function mutationhuman diseasein vivoinsightkeratinocyteloss of functionlupus cutaneouslupus-likemouse modelneutrophilnovelnucleasepatient populationpreventpseudotoxoplasmosis syndromereceptorsensorskin lesionskin organogenesistargeted treatmenttherapeutic targettherapeutically effectivetraffickingtranscriptome sequencingtype I interferon receptor
National Institute of Allergy and Infectious Diseases
CFDA Code
855
DUNS Number
603847393
UEI
MQE2JHHJW9Q8
Project Start Date
19-March-2021
Project End Date
28-February-2026
Budget Start Date
01-March-2024
Budget End Date
28-February-2025
Project Funding Information for 2024
Total Funding
$494,929
Direct Costs
$295,480
Indirect Costs
$199,449
Year
Funding IC
FY Total Cost by IC
2024
National Institute of Allergy and Infectious Diseases
$494,929
Year
Funding IC
FY Total Cost by IC
Sub Projects
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