Publications by authors named "Andrew Kimball"

14 Publications

  • Page 1 of 1

Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair.

J Immunol 2020 05 23;204(9):2503-2513. Epub 2020 Mar 23.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109;

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout ( ), we determined that MLL1 drives expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either ( ) or myeloid-specific resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation.
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http://dx.doi.org/10.4049/jimmunol.1901263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443363PMC
May 2020

Ly6CLo Monocyte/Macrophages are Essential for Thrombus Resolution in a Murine Model of Venous Thrombosis.

Thromb Haemost 2020 Feb 30;120(2):289-299. Epub 2019 Dec 30.

Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States.

Venous thrombosis (VT) resolution is a complex process, resembling sterile wound healing. Infiltrating blood-derived monocyte/macrophages (Mo/MΦs) are essential for the regulation of inflammation in tissue repair. These cells differentiate into inflammatory (CD11bLy6C) or proreparative (CD11bLy6C) subtypes. Previous studies have shown that infiltrating Mo/MΦs are important for VT resolution, but the precise roles of different Mo/MΦs subsets are not well understood. Utilizing murine models of stasis and stenosis inferior vena cava thrombosis in concert with a Mo/MΦ depletion model (CD11b-diphtheria toxin receptor [DTR]-expressing mice), we examined the effect of Mo/MΦ depletion on thrombogenesis and VT resolution. In the setting of an 80 to 90% reduction in circulating CD11bMo/MΦs, we demonstrated that Mo/MΦs are not essential for thrombogenesis, with no difference in thrombus size, neutrophil recruitment, or neutrophil extracellular traps found. Conversely, CD11bMo/MΦ are essential for VT resolution. Diphtheria toxoid (DTx)-mediated depletion after thrombus creation depleted primarily CD11bLy6C Mo/MΦs and resulted in larger thrombi. DTx-mediated depletion did not alter CD11bLy6C Mo/MΦ recruitment, suggesting a protective effect of CD11bLy6C Mo/MΦs in VT resolution. Confirmatory Mo/MΦ depletion with clodronate lysosomes showed a similar phenotype, with failure to resolve VT. Adoptive transfer of CD11bLy6C Mo/MΦs into Mo/MΦ-depleted mice reversed the phenotype, restoring normal thrombus resolution. These findings suggest that CD11bLy6C Mo/MΦs are essential for normal VT resolution, consistent with the known proreparative function of this subset, and that further study of Mo/MΦ subsets may identify targets for immunomodulation to accelerate and improve thrombosis resolution.
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http://dx.doi.org/10.1055/s-0039-3400959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365023PMC
February 2020

Sepsis Induces Prolonged Epigenetic Modifications in Bone Marrow and Peripheral Macrophages Impairing Inflammation and Wound Healing.

Arterioscler Thromb Vasc Biol 2019 11 5;39(11):2353-2366. Epub 2019 Sep 5.

From the Section of Vascular Surgery, Department of Surgery (F.M.D., A.D., A.D.J., A.S.K., A.T.O., W.J.M., K.A.G.), University of Michigan, Ann Arbor.

Objective: Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined. Approach and Results: Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3-, CD19-, Ly6G-) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow-derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL [interleukin]-1β, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow-derived macrophages and wound macrophages. This demonstrated decreased expression of , an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow-derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in compared with nonseptic controls.

Conclusions: These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1-mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.
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http://dx.doi.org/10.1161/ATVBAHA.119.312754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818743PMC
November 2019

The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.

Immunity 2019 08 23;51(2):258-271.e5. Epub 2019 Jul 23.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) β, and under diabetic conditions, this IFNβ-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.
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http://dx.doi.org/10.1016/j.immuni.2019.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703945PMC
August 2019

SIRT3 Regulates Macrophage-Mediated Inflammation in Diabetic Wound Repair.

J Invest Dermatol 2019 12 15;139(12):2528-2537.e2. Epub 2019 Jun 15.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:

Control of inflammation is critical for the treatment of nonhealing wounds, but a delicate balance exists between early inflammation that is essential for normal tissue repair and the pathologic inflammation that can occur later in the repair process. This necessitates the development of novel therapies that can target inflammation at the appropriate time during repair. Here, we found that SIRT3 is essential for normal healing and regulates inflammation in wound macrophages after injury. Under prediabetic conditions, SIRT3 was decreased in wound macrophages and resulted in dysregulated inflammation. In addition, we found that FABP4 regulates SIRT3 in human blood monocytes, and inhibition of FABP4 in wound macrophages decreases inflammatory cytokine expression, making FABP4 a viable target for the regulation of excess inflammation and wound repair in diabetes. Using a series of ex vivo and in vivo studies with genetically engineered mouse models and diabetic human monocytes, we showed that FABP4 expression is epigenetically upregulated in diabetic wound macrophages and, in turn, diminishes SIRT3 expression, thereby promoting inflammation. These findings have significant implications for controlling inflammation and promoting tissue repair in diabetic wounds.
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http://dx.doi.org/10.1016/j.jid.2019.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185380PMC
December 2019

Histone Methylation Directs Myeloid TLR4 Expression and Regulates Wound Healing following Cutaneous Tissue Injury.

J Immunol 2019 03 1;202(6):1777-1785. Epub 2019 Feb 1.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109;

Myeloid cells are critical for orchestrating regulated inflammation during wound healing. TLRs, particularly TLR4, and its downstream-signaling MyD88 pathway play an important role in regulating myeloid-mediated inflammation. Because an initial inflammatory phase is vital for tissue repair, we investigated the role of TLR4-regulated, myeloid-mediated inflammation in wound healing. In a cutaneous tissue injury murine model, we found that TLR4 expression is dynamic in wound myeloid cells during the course of normal wound healing. We identified that changes in myeloid TLR4 during tissue repair correlated with increased expression of the histone methyltransferase, mixed-lineage leukemia 1 (MLL1), which specifically trimethylates the histone 3 lysine 4 (H3K4me3) position of the TLR4 promoter. Furthermore, we used a myeloid-specific Mll1 knockout ( ) to determine MLL1 drives expression during wound healing. To understand the critical role of myeloid-specific TLR4 signaling, we used mice deficient in ( ), (), and myeloid-specific to demonstrate delayed wound healing at early time points postinjury. Furthermore, in vivo wound myeloid cells isolated from and wounds demonstrated decreased inflammatory cytokine production. Importantly, adoptive transfer of monocyte/macrophages from wild-type mice trafficked to wounds with restoration of normal healing and myeloid cell function in -deficient mice. These results define a role for myeloid-specific, MyD88-dependent TLR4 signaling in the inflammatory response following cutaneous tissue injury and suggest that MLL1 regulates TLR4 expression in wound myeloid cells.
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http://dx.doi.org/10.4049/jimmunol.1801258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401313PMC
March 2019

Murine macrophage chemokine receptor CCR2 plays a crucial role in macrophage recruitment and regulated inflammation in wound healing.

Eur J Immunol 2018 09 26;48(9):1445-1455. Epub 2018 Jun 26.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA.

Macrophages play a critical role in the establishment of a regulated inflammatory response following tissue injury. Following injury, CCR2 monocytes are recruited from peripheral blood to wound tissue, and direct the initiation and resolution of inflammation that is essential for tissue repair. In pathologic states where chronic inflammation prevents healing, macrophages fail to transition to a reparative phenotype. Using a murine model of cutaneous wound healing, we found that CCR2-deficient mice (CCR2 ) demonstrate significantly impaired wound healing at all time points postinjury. Flow cytometry analysis of wounds from CCR2 and WT mice revealed a significant decrease in inflammatory, Ly6C recruited monocyte/macrophages in CCR2 wounds. We further show that wound macrophage inflammatory cytokine production is decreased in CCR2 wounds. Adoptive transfer of mT/mG monocyte/macrophages into CCR2 and CCR2 mice demonstrated that labeled cells on days 2 and 4 traveled to wounds in both CCR2 and CCR2 mice. Further, adoptive transfer of monocyte/macrophages from WT mice restored normal healing, likely through a restored inflammatory response in the CCR2-deficient mice. Taken together, these data suggest that CCR2 plays a critical role in the recruitment and inflammatory response following injury, and that wound repair may be therapeutically manipulated through modulation of CCR2.
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http://dx.doi.org/10.1002/eji.201747400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371802PMC
September 2018

Clinical outcomes after varicose vein procedures in octogenarians within the Vascular Quality Initiative Varicose Vein Registry.

J Vasc Surg Venous Lymphat Disord 2018 07 8;6(4):464-470. Epub 2018 May 8.

Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Mich.

Background: Whereas chronic venous insufficiency and varicose veins (VVs) are a universally recognized problem, they are frequently underappreciated as major contributors to long-term morbidity in the elderly despite the increasing prevalence with age. Previous studies have demonstrated that chronic venous insufficiency and VV treatments in patients ≥65 years old yield an overall benefit; however, there have been few data as to whether octogenarians are undergoing these procedures and with what success. As such, our objectives were to investigate the procedures selected, to examine clinical outcomes after VV procedures in elderly patients ≥80 years old, and to explore complication rates (both systemic and leg specific) after VV procedures in patients ≥80 years old.

Methods: We performed a retrospective review using the Vascular Quality Initiative Varicose Vein Registry of all VV procedures performed for ≥C2 disease from January 2015 to February 2017. We divided all procedures into three age groups: patients <65 years, patients ≥65 to 79 years, and patients ≥80 years. Statistical testing included χ test for categorical variables and Student t-test for continuous variables. Two comparisons were performed: first, comparing patients <65 years old with patients ≥65 to 79 years old; and second, comparing patients ≥65 to 79 years old with patients ≥80 years old.

Results: There were a total of 12,262 procedures performed, with 8608 procedures in the patients <65 years, 3226 in patients 65 to 79 years, and 428 procedures in patients ≥80 years. A total of 22,050 veins were treated during the 12,262 procedures. Almost half of procedures (46.51%; n = 5703) had only one vein treated during a single procedure. Between age groups, the percentage of one vein treated increased as the patient's age increased, ranging from 45.39% (n = 3875) for patients <65 years to 48.55% (n = 1555) for patients between 65 and 79 years and 64.08% (n = 273) for patients ≥80 years. Patients in the group ≥80 years had an overall lower average body mass index and were more likely to be receiving anticoagulation and to undergo truncal procedures alone compared with the other groups. The group ≥80 years had a significant improvement in both Venous Clinical Severity Score (4.37 ± 4.16; P < .001) and patient-reported outcomes (8.79 ± 7.27; P < .001) from before to after the procedure. Overall complications were low in all age groups. The octogenarians had no higher risk of systemic complications.

Conclusions: Vascular specialists are performing VV procedures in octogenarians and are more likely to perform truncal only therapy. In addition, octogenarians have statistically significant improvement of Venous Clinical Severity Score and patient-reported outcomes with a low risk of complications despite more advanced venous disease at presentation.
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http://dx.doi.org/10.1016/j.jvsv.2018.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005729PMC
July 2018

Ly6C Blood Monocyte/Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus.

Arterioscler Thromb Vasc Biol 2018 05 1;38(5):1102-1114. Epub 2018 Mar 1.

From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., K.A.G.)

Objective: Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that is critical for proper healing, however, in diabetes mellitus, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown.

Approach And Results: Here, we characterized the kinetics and function of Ly6C [Lin (CD3CD19NK1.1Ter-119) Ly6GCD11b] and Ly6C [Lin (CD3CD19NK1.1Ter-119) Ly6GCD11b] monocyte/macrophage subsets in normal and diabetic wounds. Using flow-sorted -labeled Ly6C monocyte/macrophages, we show Ly6C cells transition to a Ly6C phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6C cells that fail transition to Ly6C. The second wave of Ly6C cells in diabetic wounds corresponded to a spike in MCP-1 (monocyte chemoattractant protein-1) and selective administration of anti-MCP-1 reversed the second Ly6C influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq-based transcriptome profiling was performed on flow-sorted Ly6C [LinLy6GCD11b] and Ly6C [LinLy6GCD11b] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6C cells demonstrated differences in proinflammatory and profibrotic genes compared with controls.

Conclusions: Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11bLy6C monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds.
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http://dx.doi.org/10.1161/ATVBAHA.118.310703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920725PMC
May 2018

Dysfunctional Wound Healing in Diabetic Foot Ulcers: New Crossroads.

Curr Diab Rep 2018 01 23;18(1). Epub 2018 Jan 23.

Department of Surgery, Section of Vascular Surgery, University of Michigan, 5364 Cardiovascular Center, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5867, USA.

Purpose Of Review: Diabetic foot ulcerations (DFU) affect 25% of patients with diabetes mellitus during their lifetime and constitute a major health problem as they are often recalcitrant to healing due to a constellation of both intrinsic and extrinsic factors. The purpose of this review is to (1) detail the current mechanistic understanding of DFU formation and (2) highlight future therapeutic targets.

Recent Findings: From a molecular perspective, DFUs exhibit a chronic inflammatory predisposition. In addition, increased local hypoxic conditions and impaired cellular responses to hypoxia are pathogenic factors that contribute to delayed wound healing. Finally, recent evidence suggests a role for epigenetic alterations, including microRNAs, in delayed DFU healing due to the complex interplay between genes and the environment. In this regard, notable progress has been made in the molecular and genetic understanding of DFU formation. However, further studies are needed to translate preclinical investigations into clinical therapies.
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http://dx.doi.org/10.1007/s11892-018-0970-zDOI Listing
January 2018

The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes.

Diabetes 2017 09 29;66(9):2459-2471. Epub 2017 Jun 29.

Department of Surgery, University of Michigan, Ann Arbor, MI

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-κB (NF-κB)-mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific knockout ( ) to determine the function of MLL1 in wound healing. mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-κB binding sites on inflammatory gene promoters. Of note, early wound macrophages from prediabetic mice displayed similarly decreased MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines compared with controls. Late wound macrophages from prediabetic mice demonstrated an increase in MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines. Prediabetic macrophages treated with an MLL1 inhibitor demonstrated reduced inflammation. Finally, monocytes from patients with type 2 diabetes had increased compared with control subjects without diabetes. These results define an important role for MLL1 in regulating macrophage-mediated inflammation in wound repair and identify a potential target for the treatment of chronic inflammation in diabetic wounds.
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http://dx.doi.org/10.2337/db17-0194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566299PMC
September 2017

Macrophage-Mediated Inflammation in Normal and Diabetic Wound Healing.

J Immunol 2017 07;199(1):17-24

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109;

The healing of cutaneous wounds is dependent on the progression through distinct, yet overlapping phases of wound healing, including hemostasis, inflammation, proliferation, and resolution/remodeling. The failure of these phases to occur in a timely, progressive fashion promotes pathologic wound healing. The macrophage (MΦ) has been demonstrated to play a critical role in the inflammatory phase of tissue repair, where its dynamic plasticity allows this cell to mediate both tissue-destructive and -reparative functions. The ability to understand and control both the initiation and the resolution of inflammation is critical for treating pathologic wound healing. There are now a host of studies demonstrating that metabolic and epigenetic regulation of gene transcription can influence MΦ plasticity in wounds. In this review, we highlight the molecular and epigenetic factors that influence MΦ polarization in both physiologic and pathologic wound healing, with particular attention to diabetic wounds.
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http://dx.doi.org/10.4049/jimmunol.1700223DOI Listing
July 2017

Notch Regulates Macrophage-Mediated Inflammation in Diabetic Wound Healing.

Front Immunol 2017 1;8:635. Epub 2017 Jun 1.

Department of Surgery, University of Michigan, Ann Arbor, MI, United States.

Macrophages are essential immune cells necessary for regulated inflammation during wound healing. Recent studies have identified that Notch plays a role in macrophage-mediated inflammation. Thus, we investigated the role of Notch signaling on wound macrophage phenotype and function during normal and diabetic wound healing. We found that Notch receptor and ligand expression are dynamic in wound macrophages during normal healing. Mice with a myeloid-specific Notch signaling defect ( ) demonstrated delayed early healing (days 1-3) and wound macrophages had decreased inflammatory gene expression. In our physiologic murine model of type 2 diabetes (T2D), Notch receptor expression was significantly increased in wound macrophages on day 6, following the initial inflammatory phase of wound healing, corresponding to increased inflammatory cytokine expression. This increase in and was also observed in human monocytes from patients with T2D. Further, in prediabetic mice with a genetic Notch signaling defect ( on a high-fat diet), improved wound healing was seen at late time points (days 6-7). These findings suggest that Notch is critical for the early inflammatory phase of wound healing and directs production of macrophage-dependent inflammatory mediators. These results identify that canonical Notch signaling is important in directing macrophage function in wound repair and define a translational target for the treatment of non-healing diabetic wounds.
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http://dx.doi.org/10.3389/fimmu.2017.00635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451506PMC
June 2017

The Emerging Role of NETs in Venous Thrombosis and Immunothrombosis.

Front Immunol 2016 27;7:236. Epub 2016 Jun 27.

Section of Vascular Surgery, Conrad Jobst Vascular Research Laboratories, Department of Surgery, University of Michigan , Ann Arbor, MI , USA.

Venous thrombosis (VT), a leading cause of morbidity and mortality worldwide, has recently been linked to neutrophil activation and release of neutrophil extracellular traps (NETs) via a process called NETosis. The use of various in vivo thrombosis models and genetically modified mice has more precisely defined the exact role of NETosis in the pathogenesis of VT. Translational large animal VT models and human studies have confirmed the presence of NETs in pathologic VT. Activation of neutrophils, with subsequent NETosis, has also been linked to acute infection. This innate immune response, while effective for bacterial clearance from the host by formation of an intravascular bactericidal "net," also triggers thrombosis. Intravascular thrombosis related to such innate immune mechanisms has been coined immunothrombosis. Dysregulated immunothrombosis has been proposed as a mechanism of pathologic micro- and macrovascular thrombosis in sepsis and autoimmune disease. In this focused review, we will address the dual role of NETs in the pathogenesis of VT and immunothrombosis.
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http://dx.doi.org/10.3389/fimmu.2016.00236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921471PMC
July 2016