R37AI155901

The Role of TLRs, Type II IFN, and Type III IFN in a Murine Model of Autoinflammation - Abstract

Common pathophysiological mechanisms are thought to promote the cutaneous and systemic manifestations of lupus. Thus, a better understanding of the factors that promote cutaneous lupus erythematosus (CLE) are likely to provide important insights into the pathogenesis of systemic lupus erythematosus (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 the 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 developed 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 IFN-producing Th1 cells, excessive keratinocyte death, autoantibody deposition at the dermal/epidermal border, increased expression of CXCL9, CXCL10, CXCL11, CCL8, and accumulation of plasmacytoid dendritic cells (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 on 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 these 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.

University Of Massachusetts Medical School

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93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Worcester, Massachusetts 01605 United States

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Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the End Date has been extended from 02/28/26 to 03/31/29 and the total obligations have increased 523% from $494,929 to $3,083,348.