The surface commensal microbial community has been shown to influence the function and development of the immune system, thus potentially participating in the pathophysiology of several important diseases of the skin, gut, kidney and lung. With increased appreciation that normal microbial communities exist in equilibrium with, and in many cases benefit the host, recent work has sought to better understand the mechanisms by which we permit survival of our skin commensal microbiome and how the microbiome controls mammalian immune responses. We have discovered that it was wrong to assume that bacteria are normally totally separated from us by the epidermis. Strong evidence now shows that microbial communities are in an equilibrium across the basement membrane zone and populate the dermal stroma. These observations show that the surface microbiome is in direct contact with live cells in the dermis, and therefore is in a prime position to influence local and systemic immunity. Importantly, the observation that microbes enter the dermis is not evidence for infection, rather this findings show that products made by microbes are communicating with dermal cells. The overall goal of this proposal is to understand the elements of the skin barrier that regulate microbial entry into the dermis and begin to test the hypothesis that changes in the dermal microbial community result in altered cutaneous immune responses.
Our aims are as follows:
Aim 1 : Understand the role of filaggrin in control of entry of the microbiome and immune modulation.
Aim 2 : Study how the function of the dermal microbiome is influenced by cathelicidin expression Aim 3: Characterize the dermal microbiome in Atopic Dermatitis before and after skin barrier therapy. Successful completion of these aims will provide new understanding of the skin immune system and can clarify the pathophysiology of inflammatory skin diseases such as atopic dermatitis.

Public Health Relevance

We have recently discovered that a microbiome exists in an equilibrium across the epidermis, and products of these microbes occupy compartments in the dermis. This observation demonstrates how skin commensal microbial communities can directly interact with cells of the immune system that reside in the dermis, and permits us to hypothesize that defects in the epidermal barrier can alter the microbial distribution in dermis, thus resultin in an abnormal immune response. This proposal will study how defects in the skin barrier can change bacterial entry into dermis and alter the skin's immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR064781-01A1
Application #
8696590
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2014-09-18
Project End
2019-08-31
Budget Start
2014-09-18
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$335,966
Indirect Cost
$115,966
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Williams, Michael R; Nakatsuji, Teruaki; Sanford, James A et al. (2016) Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes. J Invest Dermatol :
Nakatsuji, Teruaki; Chen, Tiffany H; Two, Aimee M et al. (2016) Staphylococcus aureus Exploits Epidermal Barrier Defects in Atopic Dermatitis to Trigger Cytokine Expression. J Invest Dermatol 136:2192-2200
Adase, Christopher A; Borkowski, Andrew W; Zhang, Ling-Juan et al. (2016) Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells. J Biol Chem 291:11635-46
Two, Aimee M; Nakatsuji, Teruaki; Kotol, Paul F et al. (2016) The Cutaneous Microbiome and Aspects of Skin Antimicrobial Defense System Resist Acute Treatment with Topical Skin Cleansers. J Invest Dermatol 136:1950-4
Gallo, Richard L; Hultsch, Thomas; Farnaes, Lauge (2016) Recognizing that the microbiome is part of the human immune system will advance treatment of both cancer and infections. J Am Acad Dermatol 74:772-4
Zhang, Ling-Juan; Sen, George L; Ward, Nicole L et al. (2016) Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-β Production by Epidermal Keratinocytes during Skin Injury. Immunity 45:119-30
Sato, Emi; Muto, Jun; Zhang, Ling-Juan et al. (2016) The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation. J Invest Dermatol 136:1449-59
Gallo, Richard L (2015) S. epidermidis influence on host immunity: more than skin deep. Cell Host Microbe 17:143-4
Ma, Gary S; Aznar, Nicolas; Kalogriopoulos, Nicholas et al. (2015) Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors. Proc Natl Acad Sci U S A 112:E2602-10
Bouslimani, Amina; Porto, Carla; Rath, Christopher M et al. (2015) Molecular cartography of the human skin surface in 3D. Proc Natl Acad Sci U S A 112:E2120-9

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