Cx3CR1 Expression Identifies Distinct Macrophage Populations That Contribute Differentially to Inflammation and Repair.

Published on Jul 1, 2019
· DOI :10.4049/IMMUNOHORIZONS.1900038
Matthew Burgess3
Estimated H-index: 3
(University of Manchester),
Kate Wicks9
Estimated H-index: 9
(University of Manchester)
+ 1 AuthorsKimberly A. Mace16
Estimated H-index: 16
(University of Manchester)
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 delayed wound healing. Long-term tissue-resident macrophages can also play a key role in the resolution of inflammation to varying degrees across different organs. In this study, we investigated different macrophage subpopulations in nondiabetic and diabetic wounds over time using Cx3CR1 eGFP transgenic mice and BM transplants. We show Cx3CR1 eGFP-hi macrophages in skin wounds are derived from long-term tissue-resident macrophages and predominantly exhibit an alternative activation state, whereas cells expressing low-intermediate Cx3CR1 eGFP are derived from the BM, contribute to both early and later stages of wound healing, and show both classical and alternative activation states. Diabetic mice showed significant differences in the dynamics of these subpopulations, which likely contribute to elevated and persisting inflammatory states over time. In particular, failure of Cx3CR1 int macrophages to mature into Cx3CR1 hi links maturation to resolution of inflammation. Thus strategies to promote macrophage maturation may be effective therapeutic tools in chronic inflammatory environments.
📖 Papers frequently viewed together
49 Citations
35 Citations
25 Citations
#1Tanja Torbica (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 8 authors...
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 environmenta...
3 CitationsSource
#1Martin Guilliams (UGent: Ghent University)H-Index: 51
#2Alexander Mildner (MDC: Max Delbrück Center for Molecular Medicine)H-Index: 36
Last. Simon Yona (UCL: University College London)H-Index: 38
view all 3 authors...
Novel experimental approaches such as fate-mapping and single-cell analysis have brought fresh insight into monocyte development and function over the past decade and helped redefine the monocyte field. Monocytes are now known to consist of multiple subsets generated through distinct developmental pathways with diverse functional specializations. Their fates under homeostatic conditions include the accumulation in peripheral reservoirs and the engraftment into certain resident macrophage pools. ...
220 CitationsSource
#1Anna Baranska (AMU: Aix-Marseille University)H-Index: 10
#1Anna Baranska (AMU: Aix-Marseille University)H-Index: 2
Last. Bernard MalissenH-Index: 111
view all 14 authors...
: Here we describe a new mouse model that exploits the pattern of expression of the high-affinity IgG receptor (CD64) and allows diphtheria toxin (DT)-mediated ablation of tissue-resident macrophages and monocyte-derived cells. We found that the myeloid cells of the ear skin dermis are dominated by DT-sensitive, melanin-laden cells that have been missed in previous studies and correspond to macrophages that have ingested melanosomes from neighboring melanocytes. Those cells have been referred to...
46 CitationsSource
#1Carlos M. Minutti (Edin.: University of Edinburgh)H-Index: 8
#2Johanna A. Knipper (Edin.: University of Edinburgh)H-Index: 7
Last. Dietmar M. W. Zaiss (Edin.: University of Edinburgh)H-Index: 28
view all 4 authors...
Macrophages are present in all tissues, either as resident cells or monocyte-derived cells that infiltrate into tissues. The tissue site largely determines the phenotype of tissue-resident cells, which help to maintain tissue homeostasis and act as sentinels of injury. Both tissue resident and recruited macrophages make a substantial contribution to wound healing following injury. In this review, we evaluate how macrophages in two fundamentally distinct tissues, i.e. the lung and the skin, diffe...
182 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
#1Tal Pecht (BGU: Ben-Gurion University of the Negev)H-Index: 7
#2Yulia Haim (BGU: Ben-Gurion University of the Negev)H-Index: 12
Last. Assaf Rudich (BGU: Ben-Gurion University of the Negev)H-Index: 69
view all 9 authors...
Background Visceral adipose tissue foam cells are increased in human obesity, and were implicated in adipose dysfunction and increased cardio-metabolic risk. In the circulation, non-classical monocytes (NCM) are elevated in obesity and associate with atherosclerosis and type 2 diabetes. We hypothesized that circulating NCM correlate and/or are functionally linked to visceral adipose tissue foam cells in obesity, potentially providing an approach to estimate visceral adipose tissue status in the ...
18 CitationsSource
#1Sohshi Morimura (UTokyo: University of Tokyo)H-Index: 11
#2Tomonori Oka (UTokyo: University of Tokyo)H-Index: 10
Last. Shinichi Sato (UTokyo: University of Tokyo)H-Index: 98
view all 4 authors...
Abstract Background CX3C chemokine receptor 1 (CX3CR1), a receptor for CX3CL1, mediates migration of inflammatory cells. Psoriasis is a common skin disorder that causes skin inflammation. The role of CX3CL1 and CX3CR1 in psoriasis remains unclear. Objective To elucidate the role of CX3CL1 and CX3CR1 in psoriasis, we assessed imiquimod-induced psoriasis-like dermatitis in CX3CR1-deficient mice. Methods We evaluated skin inflammation by assessing erythema, scaling, and ear thickness in CX3CR1 −/− ...
26 CitationsSource
#1Florent Ginhoux (Singapore Immunology Network)H-Index: 93
#2Joachim L. Schultze (University of Bonn)H-Index: 87
Last. Subhra K. Biswas (Singapore Immunology Network)H-Index: 39
view all 5 authors...
Ginhoux and colleagues discuss how recent advances in macrophage development and functional diversity indicate a multidimensional concept of macrophage ontogeny, activation and function.
388 CitationsSource
#1Johanna A. Knipper (University of Cologne)H-Index: 7
#2Sebastian Willenborg (University of Cologne)H-Index: 9
Last. Sabine A. Eming (University of Cologne)H-Index: 46
view all 15 authors...
Activation of the immune response during injury is a critical early event that determines whether the outcome of tissue restoration is regeneration or replacement of the damaged tissue with a scar. The mechanisms by which immune signals control these fundamentally different regenerative pathways are largely unknown. We have demonstrated that, during skin repair in mice, interleukin-4 receptor α (IL-4Rα)-dependent macrophage activation controlled collagen fibril assembly and that this process was...
163 CitationsSource
#1Monika Ryba-Stanisławowska (Gdańsk Medical University)H-Index: 8
#2Jolanta Myśliwska (Gdańsk Medical University)H-Index: 28
Last. Małgorzata Myśliwiec (Gdańsk Medical University)H-Index: 22
view all 4 authors...
The study aimed to analyze the CD14brightCD16+ and CD14dimCD16+ monocyte subsets in juvenile-onset complication-free diabetes mellitus type 1 in the context of their association with microvascular complications. 61 children with type 1 diabetes and 30 healthy individuals were enrolled in a study. CD14brightCD16+ and CD14dimCD16+ monocytes were quantified in peripheral blood by means of flow cytometry. At the time of sampling blood glucose concentration was taken along with biochemical measuremen...
9 CitationsSource
Cited By24
#1Marta Torregrossa (Leipzig University)
#2Ainur Kakpenova (Leipzig University)
Last. Sandra Franz (Leipzig University)H-Index: 28
view all 0 authors...
Nonhealing chronic wounds are among the most common skin disorders with increasing incidence worldwide. However, their treatment is still dissatisfying, that is why novel therapeutic concepts targeting the sustained inflammatory process have emerged. Increasing understanding of chronic wound pathologies has put macrophages in the spotlight of such approaches. Herein, we review current concepts and perspectives of therapeutic macrophage control by ECM-inspired wound dressing materials. We provide...
#1Geraldine Nouailles (Humboldt University of Berlin)H-Index: 10
#2Emanuel Wyler (MDC: Max Delbrück Center for Molecular Medicine)H-Index: 20
Last. V. M. Farztdinov (Humboldt University of Berlin)H-Index: 14
view all 25 authors...
In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and stronges...
#1Chengxin Zhou (MEE: Massachusetts Eye and Ear Infirmary)H-Index: 12
#2Fengyang Lei (MEE: Massachusetts Eye and Ear Infirmary)H-Index: 9
Last. Eleftherios I. Paschalis (MEE: Massachusetts Eye and Ear Infirmary)H-Index: 18
view all 9 authors...
Limbal stem cell (LSC) deficiency is a frequent and severe complication after chemical injury to the eye. Previous studies have assumed that this is mediated by direct chemical injury. Here we show that LSC loss can occur even without direct chemical injury to LSCs. Elevation of anterior chamber (AC) pH causes acute uveal stress, release of inflammatory cytokines at the basal limbal tissue, and subsequent LSC death. In particular, peripherally-derived CCR2+CX3CR1--monocytes cause upregulation of...
#1Imke Liebold (Bernhard Nocht Institute for Tropical Medicine)
#1Imke Liebold (Bernhard Nocht Institute for Tropical Medicine)
Last. Lidia Bosurgi (Bernhard Nocht Institute for Tropical Medicine)
view all 4 authors...
Abstract null null Functional heterogeneity in tissue macrophage populations has often been traced to developmental and spatial cues. Upon tissue damage, macrophages are exposed to soluble mediators secreted by activated cells, which shape their polarisation. Interestingly, macrophages are concomitantly exposed to a variety of different dying cells, which carry miscellaneous signals and that need to be recognised and promptly up-taken by professional phagocytes. This review discusses how differe...
#1Sonya J. Wolf (UM: University of Michigan)H-Index: 6
#2William J. Melvin (UM: University of Michigan)H-Index: 4
Last. Katherine A. Gallagher (UM: University of Michigan)H-Index: 22
view all 3 authors...
Non-healing wounds in Type 2 Diabetes (T2D) patients represent the most common cause of amputation in the US, with an associated 5-year mortality of nearly 50%. Our lab has examined tissue from both T2D murine models and human wounds in order to explore mechanisms contributing to impaired wound healing. Current published data in the field point to macrophage function serving a pivotal role in orchestrating appropriate wound healing. Wound macrophages in mice and patients with T2D are characteriz...
#1Giuseppe Caruso (University of Catania)H-Index: 29
#2Cristina Benatti (University of Modena and Reggio Emilia)H-Index: 16
Last. Filippo Caraci (University of Catania)H-Index: 43
view all 13 authors...
Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide has well-known antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of neurodegenerative disorders such as Alzheimer’s disease (AD). In this disease, peripheral infiltrating macrophages play a substantial role in the clearance of amyloid beta (Aβ) peptides from the brain. Correspondingly, in patients ...
#1Tiziana Cotechini (Queen's University)H-Index: 15
view all 3 authors...
Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coo...
#1Jefferson O. Abaricia (VCU: Virginia Commonwealth University)H-Index: 2
#2Negin Farzad (VCU: Virginia Commonwealth University)
Last. Rene Olivares-Navarrete (VCU: Virginia Commonwealth University)H-Index: 33
view all 6 authors...
Abstract As the focus of implantable biomaterials has shifted from bioinert implants to bioactive designs, recent research has highlighted the complex interactions between cell physiologic systems and material properties, particularly physical cues. From the cells known to interact with implanted biomaterials, the response of the immune system has been a critical target of study recently. Here, we review studies characterizing the response of innate immune cells to various material cues, particu...
2 CitationsSource
#1Fumihito Hikage (Sapporo Medical University)H-Index: 3
#2Anton Lennikov (MU: University of Missouri)H-Index: 11
Last. Hiroshi Ohguro (Sapporo Medical University)H-Index: 29
view all 9 authors...
PURPOSE To evaluate Nuclear Factor NF-κB (NF-κB) signaling on microglia activation, migration, and angiogenesis in laser-induced choroidal neovascularization (CNV). METHODS Nine-week-old C57BL/6 male mice were randomly assigned to IMD-0354 treated or untreated groups (5 mice, 10 eyes per group). CNV was induced with a 532-nm laser. Laser spots (power 250 mW, spot size 100 μm, time of exposure 50 ms) were created in each eye using a slit-lamp delivery system. Selective inhibitor of nuclear factor...
1 CitationsSource
#1Alessandra Julie Schuster (UFPEL: Universidade Federal de Pelotas)H-Index: 6
#2João Luiz Bittencourt de Abreu (Federal Fluminense University)
Last. Fernanda Faot (UFPEL: Universidade Federal de Pelotas)H-Index: 15
view all 6 authors...
OBJECTIVES To evaluate peri-implant bone formation of titanium implants using an in vivo rat model with and without uncontrolled diabetes mellitus (DM) to evaluate osseointegration of hydrophobic (Neoporos®) and hydrophilic (Acqua®) surfaces. MATERIALS AND METHODS 54 rats were divided into two groups: DM group (DMG) (streptozotocin-induced diabetes) and a control group (CG). Implants with hydrophobic (Neoporos®) and hydrophilic surfaces (Acqua®) were placed in the left or right tibia of animals....