Reduction of ARNT in myeloid cells causes immune suppression and delayed wound healing

Christopher Scott; James Bonner; Danqing Min; Philip Boughton; Rebecca Stokes; Kuan Minn Cha; Stacey N Walters; Kendle Maslowski; Frederic Sierro; Shane T Grey; Stephen Twigg; Susan McLennan; Jenny E Gunton

doi:10.1152/ajpcell.00306.2013

Reduction of ARNT in myeloid cells causes immune suppression and delayed wound healing

Am J Physiol Cell Physiol. 2014 Aug 15;307(4):C349-57. doi: 10.1152/ajpcell.00306.2013. Epub 2014 Jul 2.

Authors

Affiliations

¹ Diabetes and Transcription Factors Group, Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia;
² Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia;
³ St. George Clinical School, St. George Hospital, Kogarah, New South Wales, Australia; Department of Biomedical Engineering, University of Sydney, Sydney, New South Wales, Australia;
⁴ Diabetes and Transcription Factors Group, Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia;
⁵ Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia;
⁶ Department of Biochemistry, University of Lausanne, Lausanne, Switzerland;
⁷ Liver Immunology, Centenary Institute, Sydney, New South Wales, Australia;
⁸ Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia;
⁹ Diabetes and Transcription Factors Group, Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia; and Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, New South Wales, Australia jenny.gunton@sydney.edu.au j.gunton@garvan.org.au.

Abstract

Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor that binds to partners to mediate responses to environmental signals. To investigate its role in the innate immune system, floxed ARNT mice were bred with lysozyme M-Cre recombinase animals to generate lysozyme M-ARNT (LAR) mice with reduced ARNT expression. Myeloid cells of LAR mice had altered mRNA expression and delayed wound healing. Interestingly, when the animals were rendered diabetic, the difference in wound healing between the LAR mice and their littermate controls was no longer present, suggesting that decreased myeloid cell ARNT function may be an important factor in impaired wound healing in diabetes. Deferoxamine (DFO) improves wound healing by increasing hypoxia-inducible factors, which require ARNT for function. DFO was not effective in wounds of LAR mice, again suggesting that myeloid cells are important for normal wound healing and for the full benefit of DFO. These findings suggest that myeloid ARNT is important for immune function and wound healing. Increasing ARNT and, more specifically, myeloid ARNT may be a therapeutic strategy to improve wound healing.

Keywords: aryl hydrocarbon receptor nuclear translocator; deferoxamine; hypoxia-inducible factor-1α.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Aryl Hydrocarbon Receptor Nuclear Translocator / deficiency*
Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism*
Case-Control Studies
Cells, Cultured
Cytokines / genetics
Cytokines / metabolism
Deferoxamine / pharmacology
Dermatitis / genetics
Dermatitis / immunology
Dermatitis / metabolism
Dermatitis / pathology
Diabetes Complications / genetics
Diabetes Complications / immunology
Diabetes Complications / metabolism
Diabetes Complications / pathology
Diabetes Mellitus, Experimental / genetics
Diabetes Mellitus, Experimental / immunology
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Experimental / pathology
Female
Gene Expression Regulation
Genotype
Graft Survival
Humans
Immunity, Innate* / genetics
Immunocompromised Host* / genetics
Inflammation Mediators / metabolism
Integrases / genetics
Macrophage Activation
Macrophages / immunology
Macrophages / metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Middle Aged
Monocytes / immunology
Monocytes / metabolism
Muramidase / genetics
Myeloid Cells / drug effects
Myeloid Cells / immunology
Myeloid Cells / metabolism*
Phenotype
RNA, Messenger / metabolism
Skin / immunology
Skin / metabolism
Skin / pathology
Skin Transplantation
Time Factors
Transplantation Tolerance* / genetics
Wound Healing* / drug effects
Wound Healing* / genetics

Substances

ARNT protein, human
Arnt protein, mouse
Cytokines
Inflammation Mediators
RNA, Messenger
Aryl Hydrocarbon Receptor Nuclear Translocator
Cre recombinase
Integrases
Muramidase
Deferoxamine