# Kallikrein-PAR interactions in skin inflammation

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $255,432

## Abstract

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation
and autoimmunity via cleavage of protease-activated receptors (PAR)1 and PAR2. KLK6 is expressed in skin,
however its biological activities in vivo remain largely unknown. Recent work published by our lab identified
increases in KLK6 mRNA and protein in psoriasis patient lesional skin and primary KCs that decrease rapidly
with treatment and correspond with disease severity. Despite KLK6 being a highly regulated cutaneous
transcript/protein, the pathogenic significance of KLK6 in psoriasis remains unknown.
 To address this question, we genetically engineered mice to overexpress KLK6 in KCs (modeling lesional
psoriasis skin). KLK6+ mice spontaneously develop a psoriasiform skin phenotype at the histological, cellular
and molecular levels and RNAseq analyses of KLK6+ mouse skin revealed high correspondence with human
psoriasis and identified significant increases in T cell derived-cytokines Il22 and Il17a/f. To identify the
mechanisms mediating KLK6-elicited inflammation, KLK6+ mice were backcrossed with either PAR1- or
PAR2-deficient (KO) mice. KLK6+PAR2KO mice develop similar levels of skin inflammation as KLK6+ mice. In
contrast, KLK6+PAR1KO mice have attenuated skin inflammation demonstrating a critical pathogenic role for
PAR1, and not PAR2 in KLK6-induced skin inflammation. PAR1 is found on KCs and T cells and signals
through Rac1 and Rho associated kinase (ROCK)2. Using this innovative new mouse model, combined with
genetic knockout approaches, cre-lox technologies and small molecule inhibition targeting strategies coupled
with in vitro co-culture, CRISPR-Cas9 and cell signaling approaches, we will test the hypothesis that KLK6
cleaves PAR1 on KCs and T cells and activates Rac1 and ROCK2, initiating a self-sustaining proinflammatory
loop between KCs and T cells that results in a psoriasis-like proinflammatory environment. Ultimately, we will
show using human psoriasis skin organ cultures and xenograft models that interfering with new targets in this
pathway will improve human psoriasis.
 The work proposed herein will identify the cellular mechanism(s) underlying KLK6-PAR1-mediated
inflammation. Successful completion of our aims will identify KLK6 as a critical protease for psoriasis
pathogenesis and KLK6-PAR1 signaling as a new target for therapy. This pathway is profoundly different than
currently targeted cytokine pathways being investigated for the treatment of chronic inflammatory disease and
offers a new direction in psoriasis research and autoimmunity research as a whole.

## Key facts

- **NIH application ID:** 10208722
- **Project number:** 5R01AR073196-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Nicole Leanne Ward
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $255,432
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208722

## Citation

> US National Institutes of Health, RePORTER application 10208722, Kallikrein-PAR interactions in skin inflammation (5R01AR073196-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10208722. Licensed CC0.

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