Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice
Abstract
The hypothesis of this study was that cells of the monocyte/macrophage lineage (Mo/Mp) exhibit an impaired transition from pro-inflammatory to pro-healing phenotypes in wounds of diabetic mice, which contributes to deficient healing. Mo/Mp isolated from excisional wounds in non-diabetic db/+ mice exhibited a pro-inflammatory phenotype on day 5 post-injury, with high level expression of the pro-inflammatory molecules interleukin-1β, matrix metalloprotease-9 and inducible nitric oxide synthase. Wound Mo/Mp exhibited a less inflammatory phenotype on day 10 post-injury, with decreased expression of the pro-inflammatory molecules and increased expression of the alternative activation markers CD206 and CD36. In contrast, in db/db mice, the pro-inflammatory phenotype persisted through day 10 post-injury and was associated with reduced expression of insulin-like growth factor-1, transforming growth factor-β1 and vascular endothelial growth factor. Reduced levels of these growth factors in wounds of db/db mice may have contributed to impaired wound closure, reduced granulation tissue formation, angiogenesis and collagen deposition. The persistent pro-inflammatory wound Mo/Mp phenotype in db/db mice may have resulted from elevated levels of pro-inflammatory interleukin-1β and interferon-γ and reduced levels of anti-inflammatory interleukin-10 in the wound environment. Our findings are consistent with the hypothesis that dysregulation of Mo/Mp phenotypes contributes to impaired healing of diabetic wounds.
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Mp exhibit a sustained proinflammatory phenotype in wounds of diabetic mice.
“We recently demonstrated that Mp exhibit a sustained proinflammatory phenotype in wounds of diabetic mice (14)”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [14]
Bone marrow transfer from wild-type to db/db mice results in wound healing similar to db/db mice that had not received bone marrow transfer.
“Bone marrow transfer from wild-type to db/db mice resulted in wound healing that was similar to db/db mice that had not received bone marrow transfer (compare Fig. 7A–D with Fig. 6A–D and refs. 14,15)”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [14]
A persistent proinflammatory wound macrophage phenotype has been observed in diabetic humans and mice and in chronic venous ulcers.
“We and others have observed a persistent proinflammatory wound Mp phenotype in diabetic humans and mice (14,29) and in chronic venous ulcers (30).”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [14]
Recent studies have shown that macrophage phenotypes change over the different phases of tissue repair and that the sequential appearance of these phenotypes may be required for efficient repair.
“Recent studies have shown that Mp phenotypes change over the different phases of tissue repair and that the sequential appearance of these phenotypes may be required for efficient repair (11,14,29,49,50).”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [14]
Either premature changes in phenotype or delayed/impaired changes in phenotype have been associated with impaired healing.
“In fact, either premature changes in phenotype or delayed/impaired changes in phenotype have been associated with impaired healing (14,29,49).”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [14]
In mouse and human skin wounds and in injured mouse kidney, Mp expression of CD206 increases during the later stages of repair.
“Indeed, in mouse and human skin wounds and in injured mouse kidney, Mp expression of CD206 increases during the later stages of repair [33,60,61,63].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [60]
In mouse skin wounds, IL-4 mRNA and protein are not detectable at early or late time-points.
“In mouse skin wounds, IL-4 mRNA and protein are not detectable at early or late time-points [60,71].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [60]
Mp expression of mRNA and protein for these cytokines exhibits an early peak and subsequent decline after skin wounding or toxin-induced muscle injury in mice.
“Mp expression of mRNA and protein for these cytokines exhibits an early peak and subsequent decline after skin wounding [33,60] or toxin-induced muscle injury in mice [65], consistent with an early M1-like phenotype.”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [60]
The M1-associated cytokines IL-1β, TNF-α, IL-6, and IL-12 are expressed by Mp during the first few hours to days after acute injury in numerous tissues, including skin, liver, kidney, and skeletal muscle.
“The M1-associated cytokines IL-1, TNF-␣, IL-6, and IL-12 are expressed by Mp during the first few hours to days after acute injury in numerous tissues, including skin [33,60,61], liver [62], kidney [63], and skeletal muscle [57,64].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [60]
During mouse skin wound healing, Mp expression of TGF-β mRNA and protein increases over the first 7-10 days postinjury, whereas proinflammatory cytokine production decreases.
“Indeed, during mouse skin wound healing, Mp expression of TGF- mRNA and protein increases over the first 7-10 days postinjury, whereas proinflammatory cytokine production decreases [33,60], consistent with the expression of an M2a-like phenotype during the later stages of repair.”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [60]
A comprehensive in vivo macrophage phenotype cannot be deduced solely from a limited set of phenotypic markers.
“Additionally, a comprehensive in vivo Mp phenotype cannot be deduced solely from a limited set of phenotypic markers, as different M2a-associated genes or proteins can exhibit entirely different temporal regulation and can be coexpressed with M1-associated markers [19,25,33,60,78].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [60]
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- Authors
- Mirza, R., & Koh, T. J.
- Affiliations
- University of Illinois Chicago (US)
- Corresponding author
- Koh, Timothy J.
- ORCID
- Koh, Timothy J.
- Venue
- Cytokine
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 56
- Issue
- 2
- Pages
- 256-264
- ISSN
- 1043-4666 (ISSN-L)
- OpenAlex
- W2057864569
- Semantic Scholar
- 1f48248e2a91668cf09529b853c24fad07f4f0ba
- Cited by
- 342
- References
- 41
- Citations by year
- 2026: 20 · 2025: 32 · 2024: 29 · 2023: 35 · 2022: 30 · 2021: 23 · 2020: 29 · 2019: 25 · 2018: 21 · 2017: 21 · 2016: 18 · 2015: 21 · 2014: 17 · 2013: 10 · 2012: 10
- FWCI
- 11.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cytokine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Illinois at Chicago
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetic Foot Ulcer Assessment and Management
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- diabetic wound healing, macrophage polarization, inflammatory macrophages, alternative macrophage activation, db/db mice, IL-1β, MMP-9, inducible nitric oxide synthase, CD206, CD36, insulin-like growth factor I, TGF-β1, vascular endothelial growth factor, angiogenesis, granulation tissue, collagen deposition, interferon-gamma, IL-10
- MeSH terms
- Animals, Base Sequence, Diabetes Mellitus, Experimental, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Macrophages, Monocytes, Wound Healing, Wounds and Injuries, Immunophenotyping, Polymerase Chain Reaction, DNA Primers, Mice
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