Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes: a recipe for impaired wound healing

Mohan R Dasu; Sandra R Ramirez; Thi Dinh La; Farzam Gorouhi; Chuong Nguyen; Benjamin R Lin; Chelcy Mashburn; Heather Stewart; Thomas R Peavy; Jan A Nolta; Roslyn R Isseroff

doi:10.5966/sctm.2013-0200

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Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes: a recipe for impaired wound healing

Journal article

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Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes: a recipe for impaired wound healing

Mohan R Dasu, Sandra R Ramirez, Thi Dinh La, Farzam Gorouhi, Chuong Nguyen, Benjamin R Lin, Chelcy Mashburn, Heather Stewart, Thomas R Peavy, Jan A Nolta, …

Stem cells translational medicine, Vol.3(6), pp.745-759

06/2014

DOI: https://doi.org/10.5966/sctm.2013-0200

Handle:

https://hdl.handle.net/20.500.12741/rep:3847

PMCID: PMC4039457

PMID: 24760207

Abstract

Phosphorylation

Toll-Like Receptor 2 - agonists

Lipopeptides - pharmacology

Skin - metabolism

Humans

Male

G-Protein-Coupled Receptor Kinase 2 - metabolism

Receptors, Adrenergic, beta-2 - drug effects

Skin - injuries

Stem Cell Transplantation

Time Factors

Mesenchymal Stem Cells - drug effects

Interleukin-6 - metabolism

Mesenchymal Stem Cells - metabolism

Wound Healing - drug effects

Skin - pathology

Adrenergic beta-Antagonists - blood

Receptor Cross-Talk

Mice, Inbred C57BL

Cells, Cultured

Adrenergic beta-Agonists - pharmacology

Toll-Like Receptor 2 - metabolism

Receptors, Adrenergic, beta-2 - metabolism

Mesenchymal Stem Cells - pathology

Keratinocytes - pathology

Animals

Keratinocytes - drug effects

Keratinocytes - metabolism

Cell Communication - drug effects

Mice

Myeloid Differentiation Factor 88 - metabolism

Epinephrine - metabolism

Epinephrine - pharmacology

Cell Movement

Previous studies demonstrate that skin wounds generate epinephrine (EPI) that can activate local adrenergic receptors (ARs), impairing healing. Bacterially derived activators of Toll-like receptors (TLRs) within the wound initiate inflammatory responses and can also impair healing. In this study, we examined the hypothesis that these two pathways crosstalk to one another, using EPI and macrophage-activating lipopeptide-2 (MALP2) to activate ARs and TLR2, respectively, in human bone marrow-derived mesenchymal stem cells (BM-MSCs) and neonatal keratinocytes (NHKs). BM-MSCs exposed to EPI significantly (p < .05) increased TLR2 message (sevenfold BM-MSCs), TLR2 protein (twofold), and myeloid differentiation factor 88 (MyD88) (fourfold). Conversely, activation of TLR2 by MALP2 in these cells increased β2-AR message (twofold in BM-MSCs, 2.7-fold in NHKs), β2-AR protein (2.5-fold), phosphorylation of β-AR-activated kinase (p-BARK, twofold), and induced release of EPI from both cell types (twofold). Treating cells with EPI and MALP2 together, as would be encountered in a wound, increased β2-AR and p-BARK protein expression (sixfold), impaired cell migration (BM-MSCs- 21%↓ and NHKs- 60%↓, p < .002), and resulted in a 10-fold (BM-MSCs) and 51-fold (NHKs) increase in release of IL-6 (p < .001) responses that were remarkably reduced by pretreatment with β2-AR antagonists. In vivo, EPI-stressed animals exhibited impaired healing, with elevated levels of TLR2, MyD88, and IL-6 in the wounds (p < .05) relative to nonstressed controls. Thus, our data describe a recipe for decreasing cell migration and exacerbating inflammation via novel crosstalk between the adrenergic and Toll-like receptor pathways in BM-MSCs and NHKs.

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Title: Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes: a recipe for impaired wound healing
Creators: Mohan R Dasu - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA rrisseroff@ucdavis.edu rkdasu@ucdavis.edu rkmdasu@gmail.com
Sandra R Ramirez - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA
Thi Dinh La - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA
Farzam Gorouhi - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA
Chuong Nguyen - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA
Benjamin R Lin - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA
Chelcy Mashburn - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA
Heather Stewart - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA
Thomas R Peavy - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA
Jan A Nolta - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA
Roslyn R Isseroff - Department of Dermatology and Institute for Regenerative Cures, University of California, Davis, California, USA; Department of Biological Sciences, California State University, Sacramento, California, USA; Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Sacramento, California, USA rrisseroff@ucdavis.edu rkdasu@ucdavis.edu rkmdasu@gmail.com
Academic Unit: Department of Biological Sciences
Publisher: United States
Publication Details: 06/2014
Grant note: R34 AI080604 / NIAID NIH HHS R01 GM099688 / NIGMS NIH HHS T32 GM099608 / NIGMS NIH HHS R21 AI080604 / NIAID NIH HHS 1R01GM099688 / NIGMS NIH HHS R33 AI080604 / NIAID NIH HHS
Identifiers: 99257847577301671; https://hdl.handle.net/20.500.12741/rep:3847; https://doi.org/10.5966/sctm.2013-0200
Language: English