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      Pro-Inflammatory Chemokine CCL2 (MCP-1) Promotes Healing in Diabetic Wounds by Restoring the Macrophage Response

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          Abstract

          Prior studies suggest that the impaired healing seen in diabetic wounds derives from a state of persistent hyper-inflammation characterized by harmful increases in inflammatory leukocytes including macrophages. However, such studies have focused on wounds at later time points (day 10 or older), and very little attention has been given to the dynamics of macrophage responses in diabetic wounds early after injury. Given the importance of macrophages for the process of healing, we studied the dynamics of macrophage response during early and late phases of healing in diabetic wounds. Here, we report that early after injury, the diabetic wound exhibits a significant delay in macrophage infiltration. The delay in the macrophage response in diabetic wounds results from reduced Chemokine (C-C motif) ligand 2 (CCL2) expression. Importantly, one-time treatment with chemoattractant CCL2 significantly stimulated healing in diabetic wounds by restoring the macrophage response. Our data demonstrate that, rather than a hyper-inflammatory state; the early diabetic wound exhibits a paradoxical and damaging decrease in essential macrophage response. Our studies suggest that the restoration of the proper kinetics of macrophage response may be able to jumpstart subsequent healing stages. CCL2 chemokine-based therapy may be an attractive strategy to promote healing in diabetic wounds.

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          Most cited references 31

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          Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice.

           X Weng,  R Tepper,  G Duyk (1996)
          OB-R is a high affinity receptor for leptin, an important circulating signal for the regulation of body weight. We identified an alternatively spliced transcript that encodes a form of mouse OB-R with a long intracellular domain. db/db mice also produce this alternatively spliced transcript, but with a 106 nt insertion that prematurely terminates the intracellular domain. We further identified G --> T point mutation in the genomic OB-R sequence in db/db mice. This mutation generates a donor splice site that converts the 106 nt region to a novel exon retained in the OB-R transcript. We predict that the long intracellular domain form of OB-R is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of OB-R leads to the severe obese phenotype found in db/db mice.
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            Wound repair at a glance.

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              Why chronic wounds will not heal: a novel hypothesis.

              The present paper presents a hypothesis aimed at explaining why venous leg ulcers, pressure ulcers, and diabetic foot ulcers develop into a chronic state. We propose that the lack of proper wound healing is at least in part caused by inefficient eradication of infecting, opportunistic pathogens, a situation reminiscent of chronic Pseudomonas aeruginosa infections found in patients suffering from cystic fibrosis (CF). We have analyzed sections from chronic wounds by fluorescence in situ hybridization and found distinct microcolonies--the basal structures of bacterial biofilms. Several researchers have previously reported that another important hallmark of biofilm formation is development of increased tolerance to various antimicrobial measures and treatments. Furthermore, the immune response to infecting bacteria in the cystic fibrosis lung is dominated by polymorphonuclear neutrophils (PMNs), and we have recently shown that in vitro biofilms of P. aeruginosa produce a shielding mechanism that offers protection from the phagocytic activity of PMNs. We hypothesize that the presence of P. aeruginosa in biofilms, and the lack of concomitant elimination by attended PMNs, are the main causes of inefficient eradication by antibiotic treatment and antimicrobial activity of the innate immune system, respectively.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                11 March 2014
                : 9
                : 3
                Affiliations
                [1 ]Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America
                [2 ]Rush University Cancer Center, Rush University Medical Center, Chicago, Illinois, United States of America
                [3 ]Department of Dermatology, Rush University Medical Center, Chicago, Illinois, United States of America
                [4 ]Developmental Center for AIDS Research, Rush University Medical Center, Chicago, Illinois, United States of America
                [5 ]Department of Pharmacology, Rush University Medical Center, Chicago, Illinois, United States of America
                [6 ]Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, United States of America
                Shanghai Medical College, China
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SHS LD AZ. Performed the experiments: SW VJ EJH DB GS BB SQ. Analyzed the data: SW VJ EJH DB GS. Contributed reagents/materials/analysis tools: BB LD AZ CZ SHS. Wrote the paper: SHS.

                Article
                PONE-D-13-35162
                10.1371/journal.pone.0091574
                3950222

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 8
                Funding
                This work was supported by The Rush University Committee on Research, Young Investigator Award Fund #: 31184 to (SHS) and the National Institute of Health grant R21NR013876-0 to (CZ & SHS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Endocrine System
                Diabetic Endocrinology
                Immune Physiology
                Immune Cells
                Cytokines
                Skin
                Immunology
                Immune Cells
                Monocytes
                Immune System
                Cytokines
                Immune Response
                Model Organisms
                Animal Models
                Mouse
                Medicine
                Anatomy and Physiology
                Endocrine System
                Diabetic Endocrinology
                Endocrinology
                Diabetic Endocrinology

                Uncategorized

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