# Mast cells in skin innate immune defense

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $509,367

## Abstract

ABSTRACT
We have demonstrated that mast cells entering the skin change phenotype triggered by contact with dermal
fibroblasts (DF). In the skin, Mast Cells (MCs) down regulate their TLR2 and increase the expression of genes
that downregulate the NFB, a known inflammatory pathway. This contributes to maintaining skin homeostasis
and makes mast cell tolerant to commensal bacteria. We found that DKK2, a specific protein secreted by DFs,
modulates the huMC NF–B pathway, by increasing gene expression of TNFAIP3 (A20) and NFKBIA in
huMCs. This modulation results in a decreased inflammatory response to commensal bacteria. In this
proposal, we will clarify the mechanisms of DF - MC signaling, which induces a MC skin tolerant phenotype.
This is an important mechanism for skin inflammation and atopic dermatitis (AD) in particular. We will present
preliminary data that show that in AD, DFs fail to maintain human MC (huMC) tolerance to commensal bacteria
which allows huMC to release proinflammatory cytokines. The idea that inflammatory diseases develop
because MC tolerance is broken represents a shift in science paradigm. This work will identify the mechanisms
underlying the roles of huMCs in building and breaking tolerance to the skin’s rich environment.
We propose the followings:
 1. To determine whether TNFAIP3 (A20) and NFKBIA in human MCs are required for preventing
 proinflammatory interleukin responses (tolerance) to commensal supernatant. In Aim 1 of this
 proposal, we will use a variety of structural, biophysical, biochemical, and functional assays to
 determine how dermal MCs collaborate with DFs. More specifically, we will analyze the MC expression
 of the NF–B related genes, TNFAIP3 (A20) and NFKBIA, as well as receptors related to the innate
 immune system in dermal huMCs.
 2. To confirm that MC tolerance can be induced by DKK2 from DFs
 In Aim 2, we will determine whether DF DKK2 is required for inducing huMC tolerance to commensal
 supernatant and whether different DF sub-populations vary in their ability to induce tolerance in huMCs.
 3. To confirm that DF-induced MC tolerance to commensal bacteria is critical for suppressing
 human skin inflammation.
 In Aim 3 of this proposal we will look at the consequences of the failure of huMCs to maintain tolerance
 and their role in skin inflammation, specifically in Atopic Dermatitis skin.

## Key facts

- **NIH application ID:** 10333319
- **Project number:** 5R01AI093957-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Anna Di Nardo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $509,367
- **Award type:** 5
- **Project period:** 2011-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333319

## Citation

> US National Institutes of Health, RePORTER application 10333319, Mast cells in skin innate immune defense (5R01AI093957-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10333319. Licensed CC0.

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