Type I interferons (IFNs) are increased in cutaneous lupus erythematosus (CLE) lesions and contribute to disease pathogenesis, yet skin-intrinsic sources of type I IFN have not been explored. Keratinocytes are the primary source of IFN kappa (?), a type I IFN that is a genetic risk factor for cutaneous lupus, significantly upregulated in CLE skin lesions, and is produced more robustly from systemic lupus erythematosus (SLE) vs. control keratinocytes. Importantly, neutralization of IFN? signaling eliminates hyper-inflammatory responses to ultraviolet light and toll-like receptor agonists in SLE keratinocytes. Thus, IFN? primes the abundant cutaneous inflammatory response in SLE. It is consequently critical to understand the regulation of IFN? and its role in regulation of inflammatory cytokine production and recruitment of cellular infiltrates as IFN? may prove to be a specific target for treatment or prevention of cutaneous lesions, and its specific inhibition may consequently avoid side effects from systemic blockade of other type I IFNs. The overall objective for this project is to define the mechanisms and consequences of aberrant regulation of IFN? in SLE skin. It is hypothesized that hyper- production of IFN? is a mechanism by which SLE keratinocytes are primed to overproduce inflammatory cytokines and chemokines and consequently increase inflammatory responses and that IFN? will thus serve as a specific and viable target for prevention or treatment of SLE-associated skin lesions. The proposal will address this hypothesis through investigation of the following:
Aim 1 : Identify the mechanisms underlying increased production of IFN? in lupus keratinocytes. Regulation of IFN? by IFNs, STING signaling and methylation changes will be explored in control and SLE (including consideration of CLE subtypes) keratinocytes.
Aim 2 : Identify the mechanisms by which keratinocyte-produced IFN? promotes inflammatory responses. Effects of IFN? on keratinocyte IFN production, monocyte, dendritic cell, and plasmacytoid dendritic cell recruitment and activation in vitro and in vivo will be explored.
Aim 3 : Identify the in vivo impact of IFN? overexpression on cutaneous inflammation and systemic autoimmunity. Characterization of cutaneous and systemic autoimmunity and response to cutaneous inflammatory stimuli will be completed in a novel mouse that overexpresses IFN? in the epidermis. Completion of this work will support a paradigm shift in which keratinocyte-derived IFN? is recognized as an important step for priming and persistence of a hyper-inflammatory response in SLE skin and is identified as a specific target for future treatment and prevention of SLE-associated skin lesions.

Public Health Relevance

Cutaneous lupus lesions are disfiguring, difficult to treat, and often associated with flares of systemic lupus that lead to organ damage and disability. This project will uncover novel mechanisms that drive the development of cutaneous lupus lesions and will ultimately lead to new preventative and therapeutic strategies for this devastating disease. Discoveries made through this research are directly relevant to the NIH's mission to foster fundamental discoveries and their applications to protect and improve public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR071384-02
Application #
9569251
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2017-09-21
Project End
2022-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Sarkar, Mrinal K; Hile, Grace A; Tsoi, Lam C et al. (2018) Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann Rheum Dis 77:1653-1664
Hile, Grace A; Gudjonsson, Johann E; Kahlenberg, J Michelle (2018) The influence of interferon on healthy and diseased skin. Cytokine :
Swindell, William R; Beamer, Maria A; Sarkar, Mrinal K et al. (2018) RNA-Seq Analysis of IL-1B and IL-36 Responses in Epidermal Keratinocytes Identifies a Shared MyD88-Dependent Gene Signature. Front Immunol 9:80
Wolf, Sonya J; Theros, Jonathan; Reed, Tammi J et al. (2018) TLR7-Mediated Lupus Nephritis Is Independent of Type I IFN Signaling. J Immunol 201:393-405