Chronic Inflammation in Response to Injury: Retention of Myeloid Cells in Injured Tissue Is Driven by Myeloid Cell Intrinsic Factors

Published on Jul 1, 2019in Journal of Investigative Dermatology7.143
· DOI :10.1016/J.JID.2018.12.030
Tanja Torbica3
Estimated H-index: 3
(University of Manchester),
Kate Wicks9
Estimated H-index: 9
(University of Manchester)
+ 5 AuthorsKimberly A. Mace16
Estimated H-index: 16
(University of Manchester)
Chronic inflammation is a hallmark of impaired healing in a plethora of tissues, including skin, and is associated with aging and diseases such as diabetes. Diabetic chronic skin wounds are characterized by excessive myeloid cells that display an aberrant phenotype, partially mediated by stable intrinsic changes induced during hematopoietic development. However, the relative contribution of myeloid cell–intrinsic factors to chronic inflammation versus aberrant signals from the local environmental was unknown. Moreover, identification of myeloid cell intrinsic factors that contribute to chronic inflammation in diabetic wounds remained elusive. Here we show that Gr-1+CD11b+ myeloid cells are retained specifically within the presumptive granulation tissue region of the wound at a higher density in diabetic mice and associate with endothelial cells at the site of injury with a higher frequency than in nondiabetic mice. Adoptive transfer of myeloid cells demonstrated that aberrant wound retention is due to myeloid cell intrinsic factors and not the local environment. RNA sequencing of bone marrow and wound-derived myeloid cells identified Selplg as a myeloid cell intrinsic factor that is deregulated in chronic wounds. In vivo blockade of this protein significantly accelerated wound healing in diabetic mice and may be a potential therapeutic target in chronic wounds and other chronic inflammatory diseases.
📖 Papers frequently viewed together
70 Citations
7 Authors (Junwang Xu, ..., Kenneth W. Liechty)
132 Citations
#1Lusine Khondkaryan (NAS: National Academy of Sciences)H-Index: 4
#2Sona Margaryan (NAS: National Academy of Sciences)H-Index: 4
Last. Gayane Manukyan (Armenian National Academy of Sciences)H-Index: 3
view all 4 authors...
Type 2 diabetes mellitus (T2DM) is a severe health problem worldwide, reaching epidemic levels. High susceptibility to infections of T2DM patients indicates dysregulated immune responses to pathogens. However, innate immune responses, including monocyte functions, in T2DM are poorly investigated. Therefore, in this study we aimed to assess lipopolysaccharide- (LPS-) induced immune responses of circulating monocytes from T2DM patients. The results showed that monocytes from T2DM were hyporesponsi...
14 CitationsSource
#1Ivan S. YevshinH-Index: 7
#2Ruslan N. Sharipov (NSU: Novosibirsk State University)H-Index: 11
Last. Fedor A. KolpakovH-Index: 14
view all 5 authors...
: GTRD-Gene Transcription Regulation Database ( a database of transcription factor binding sites (TFBSs) identified by ChIP-seq experiments for human and mouse. Raw ChIP-seq data were obtained from ENCODE and SRA and uniformly processed: (i) reads were aligned using Bowtie2; (ii) ChIP-seq peaks were called using peak callers MACS, SISSRs, GEM and PICS; (iii) peaks for the same factor and peak callers, but different experiment conditions (cell line, treatment, etc.), wer...
140 CitationsSource
#1Hadeel Al Sadoun (University of Manchester)H-Index: 3
#2Matthew Burgess (University of Manchester)H-Index: 3
Last. Kimberly A. Mace (University of Manchester)H-Index: 16
view all 4 authors...
The regulated differentiation of macrophages (mφs) and their subsequent activation into proinflammatory or prohealing subtypes is critical for efficient wound healing. Chronic wounds such as diabetic (db) ulcers are associated with dysregulation of macrophage function. Whereas non-db mφs polarize to an M2-like, prohealing phenotype during the late stages of healing, db-derived mφs continue to display an M1-like, proinflammatory, or a mixed M1-like/M2-like phenotype. We have previously shown that...
13 CitationsSource
#1Lionel B. Ivashkiv (HSS: Hospital for Special Surgery)H-Index: 81
#2Sung Ho Park (HSS: Hospital for Special Surgery)H-Index: 18
Epigenetics in the context of cell differentiation and activation refers to mechanisms that regulate and potentially stabilize gene expression in response to developmental and environmental cues. Epigenetic regulation is mediated by posttranslational modification of DNA or chromatin and by noncoding RNAs. In myeloid cells, the predominant focus of research on epigenetic mechanisms has been chromatin-mediated regulation of macrophages, which will be the focus of this review ( 1 – 3 ). Differentia...
14 CitationsSource
#1Ann De Becker (Vrije Universiteit Brussel)H-Index: 12
#2Ivan Van Riet (Vrije Universiteit Brussel)H-Index: 27
Mesenchymal stromal cells (MSCs) are currently being investigated for use in a wide variety of clinical applications. For most of these applications, systemic delivery of the cells is preferred. However, this requires the homing and migration of MSCs to a target tissue. Although MSC homing has been described, this process does not appear to be highly efficacious because only a few cells reach the target tissue and remain there after systemic administration. This has been ascribed to low expressi...
232 CitationsSource
#1Julian F. Guest ('KCL': King's College London)H-Index: 33
#2Nadia Ayoub (NU: Northwood University)H-Index: 4
Last. Peter Vowden (University of Bradford)H-Index: 30
view all 8 authors...
Objective To estimate the prevalence of wounds managed by the UK9s National Health Service (NHS) in 2012/2013 and the annual levels of healthcare resource use attributable to their management and corresponding costs. Methods This was a retrospective cohort analysis of the records of patients in The Health Improvement Network (THIN) Database. Records of 1000 adult patients who had a wound in 2012/2013 (cases) were randomly selected and matched with 1000 patients with no history of a wound (contro...
310 CitationsSource
#1Kate Wicks (University of Manchester)H-Index: 9
#2Tanja Torbica (University of Manchester)H-Index: 3
Last. Kimberly A. Mace (University of Manchester)H-Index: 16
view all 6 authors...
Recruitment of innate immune cells from the bone marrow (BM) to an injury site is required for effective repair. In diabetes, this process is altered, leading to excessive recruitment and retention of dysfunctional myeloid cells that fail to promote angiogenesis, prolong inflammation, and block healing. The aberrant myeloid phenotype is partially mediated by stable intrinsic changes to developing cells in the BM that are induced by the diabetic (db) environment, but the exact mechanisms remain l...
10 CitationsSource
#1Katherine A. Gallagher (UM: University of Michigan)H-Index: 22
#2Amrita Joshi (UM: University of Michigan)H-Index: 20
Last. Steven L. Kunkel (UM: University of Michigan)H-Index: 157
view all 12 authors...
Classically activated (M1) macrophages are known to play a role in the development of chronic inflammation associated with impaired wound healing in type 2 diabetes (T2D); however, the mechanism responsible for the dominant proinflammatory (M1) macrophage phenotype in T2D wounds is unknown. Since epigenetic enzymes can direct macrophage phenotypes, we assessed the role of histone methylation in bone marrow (BM) stem/progenitor cells in the programming of macrophages toward a proinflammatory phen...
104 CitationsSource
#1Pauline Bannon (University of Manchester)H-Index: 1
#2Sally Wood (University of Manchester)H-Index: 1
Last. Kimberly A. Mace (University of Manchester)H-Index: 16
view all 6 authors...
Acute inflammation in response to injury is a tightly regulated process by which subsets of leukocytes are recruited to the injured tissue and undergo behavioural changes that are essential for effective tissue repair and regeneration. The diabetic wound environment is characterised by excessive and prolonged inflammation that is linked to poor progression of healing and, in humans, the development of diabetic foot ulcers. However, the underlying mechanisms contributing to excessive inflammation...
70 CitationsSource
#1Fredirick Mashili (KI: Karolinska Institutet)H-Index: 6
#2Alexander V. Chibalin (KI: Karolinska Institutet)H-Index: 58
Last. Juleen R. Zierath (KI: Karolinska Institutet)H-Index: 105
view all 4 authors...
Signal transducer and activator of transcription 3 (STAT3) is involved in cytokine- and nutrient-induced insulin resistance. The role of STAT3 in the development of skeletal muscle insulin resistance and type 2 diabetes (T2D) pathogenesis is incompletely defined. We tested the hypothesis that STAT3 signaling contributes to skeletal muscle insulin resistance in T2D. Protein abundance and phosphorylation of STAT3 signaling molecules were determined in skeletal muscle biopsy specimens from BMI- and...
68 CitationsSource
Cited By3
#1Michela Grillo (University of Nottingham)
#2Carolyn Palmer (University of Nottingham)
Last. Peter E. Shaw (University of Nottingham)H-Index: 36
view all 7 authors...
Reactive oxygen species are bona fide intracellular second messengers that influence cell metabolism and aging by mechanisms that are incompletely resolved. Mitochondria generate superoxide that is dis-mutated to hydrogen peroxide, which in turn oxidises cysteine-based enzymes such as phosphatases, peroxiredoxins and redox-sensitive transcription factors to modulate their activity. Signal Transducer and Activator of Transcription 3 (Stat3) has been shown to participate in an oxidative relay with...
#1Matthew Burgess (University of Manchester)H-Index: 3
#2Kate Wicks (University of Manchester)H-Index: 9
Last. Kimberly A. Mace (University of Manchester)H-Index: 16
view all 4 authors...
Bone marrow (BM)–derived classical monocytes are critical to wound repair, where they differentiate into macrophages and purge foreign materials and dead cells while also laying the framework for tissue repair and regeneration. A subset of this recruited population persists in the wound and acquires alternative activation states to promote cell proliferation and matrix remodeling. In diabetes, this phenotypic switch is impaired and inflammation persists in an elevated state, contributing to dela...
24 CitationsSource
#1Juan Feng (SYSU: Sun Yat-sen University)H-Index: 6
#2Chang Dong (SYSU: Sun Yat-sen University)H-Index: 3
Last. Weiwei Qi (SYSU: Sun Yat-sen University)H-Index: 10
view all 13 authors...
The accumulation of M1-polarized macrophages and excessive inflammation are important in the pathogenesis of diabetic foot ulcer (DFU). However, the underlying mechanism of DFU pathogenesis and the crucial regulators of DFU are less well known. Our previous study reported that kallikrein-binding protein (KBP), an angiogenesis inhibitor, was significantly upregulated in diabetic patients compared to its levels in controls. The effects of KBP on monocyte chemotaxis and macrophage M1 polarization w...
10 CitationsSource