Abstract
The process of inflammation is orchestrated by macrophages, according to their state of differentiation: thus, classically activated (M1) macrophages initiate the process by elaborating proinflammatory cytokines and reactive oxygen species, whereas the latter phase is controlled by alternatively activated macrophages (M2) to resolve inflammation and promote tissue remodelling with the release of growth factors. In a simple human inflammatory response, such as acute crystal arthropathy, macrophages progress linearly through M1 and M2 phases; however, in chronic inflammatory responses, such as atherosclerosis and Diabetic Nephropathy (DN), both M1 and M2 macrophages may coexist, leading to persistent inflammation and fibrosis.
A key macrophage receptor that regulates conversion from M1 to M2 is CD163, the hemoglobin scavenger receptor. Scavenging of hemoglobin:haptoglobin (Hb:Hp) complexes via CD163 leads to nuclear translocation of the transcription factor Nrf2 (NF-E2-related factor 2), upregulation of heme oxygenase (HO)-1 cytoprotective protein, and release of interleukin (IL)-10 anti-inflammatory cytokine; IL-10 is then linked in a positive feedback loop to further CD163 expression. The potency of this M1/M2 switching pathway is underscored by the fact that human Hp2 polymorphisms are associated with worsened clinical outcomes for diabetic complications, including DN. Parallel observations in animals show that HO-1 activation by hemin protects against DN in rodent models of diabetes.
This review discusses the concept that Nrf2/HO-1 acts as a ‘therapeutic funnel’ through which a range of natural and synthetic anti-oxidants may drive M1 to M2 switching and improved kidney function in diabetes. We also discuss our observations on the evolution of M1/M2 phenotypes in a human model of wound healing which has presented intriguing potential drug targets for DN, such as eotaxin/CCR3.
Keywords: Macrophage, heme oxygenase, pharmacologic target, kidney injury, reactive oxygen species, diabetic nephropathy.
Current Pharmaceutical Design
Title:M1/M2 Macrophages in Diabetic Nephropathy: Nrf2/HO-1 as Therapeutic Targets
Volume: 24 Issue: 20
Author(s): Robert Clive Landis*, Kim R. Quimby and Andre R. Greenidge
Affiliation:
- Edmund Cohen Laboratory for Vascular Research, George Alleyne Chronic Disease Research Centre, The University of the West Indies, Barbados BB11115,West Indies
Keywords: Macrophage, heme oxygenase, pharmacologic target, kidney injury, reactive oxygen species, diabetic nephropathy.
Abstract: The process of inflammation is orchestrated by macrophages, according to their state of differentiation: thus, classically activated (M1) macrophages initiate the process by elaborating proinflammatory cytokines and reactive oxygen species, whereas the latter phase is controlled by alternatively activated macrophages (M2) to resolve inflammation and promote tissue remodelling with the release of growth factors. In a simple human inflammatory response, such as acute crystal arthropathy, macrophages progress linearly through M1 and M2 phases; however, in chronic inflammatory responses, such as atherosclerosis and Diabetic Nephropathy (DN), both M1 and M2 macrophages may coexist, leading to persistent inflammation and fibrosis.
A key macrophage receptor that regulates conversion from M1 to M2 is CD163, the hemoglobin scavenger receptor. Scavenging of hemoglobin:haptoglobin (Hb:Hp) complexes via CD163 leads to nuclear translocation of the transcription factor Nrf2 (NF-E2-related factor 2), upregulation of heme oxygenase (HO)-1 cytoprotective protein, and release of interleukin (IL)-10 anti-inflammatory cytokine; IL-10 is then linked in a positive feedback loop to further CD163 expression. The potency of this M1/M2 switching pathway is underscored by the fact that human Hp2 polymorphisms are associated with worsened clinical outcomes for diabetic complications, including DN. Parallel observations in animals show that HO-1 activation by hemin protects against DN in rodent models of diabetes.
This review discusses the concept that Nrf2/HO-1 acts as a ‘therapeutic funnel’ through which a range of natural and synthetic anti-oxidants may drive M1 to M2 switching and improved kidney function in diabetes. We also discuss our observations on the evolution of M1/M2 phenotypes in a human model of wound healing which has presented intriguing potential drug targets for DN, such as eotaxin/CCR3.
Export Options
About this article
Cite this article as:
Landis Clive Robert*, Quimby R. Kim and Greenidge R. Andre , M1/M2 Macrophages in Diabetic Nephropathy: Nrf2/HO-1 as Therapeutic Targets, Current Pharmaceutical Design 2018; 24 (20) . https://dx.doi.org/10.2174/1381612824666180716163845
DOI https://dx.doi.org/10.2174/1381612824666180716163845 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Protective Effect of CCR5 Delta-32 Allele Against HIV-1 in Mexican Women
Current HIV Research Patent Selections:
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Pharmacotherapy in Systemic Lupus Erythematosus
Current Rheumatology Reviews Carotenoids of Microalgae Used in Food Industry and Medicine
Mini-Reviews in Medicinal Chemistry Combinations of Renin-Angiotensin-Aldosterone System Antagonists:True Advantages?
Current Pharmaceutical Design Renal Nerve Ablation for Hypertensive Patients with Chronic Kidney Disease
Current Vascular Pharmacology 3,4-DGE is Important for Side Effects in Peritoneal Dialysis What About its Role in Diabetes
Current Medicinal Chemistry Role of Asymmetric Dimethylarginine in Cardiorenal Syndrome
Current Pharmaceutical Design Hydrogen Sulfide in Diabetic Complications: Focus on Molecular Mechanisms
Endocrine, Metabolic & Immune Disorders - Drug Targets Metabolic Syndrome X is a Low-Grade Systemic Inflammatory Condition with its Origins in the Perinatal Period
Current Nutrition & Food Science Gene/Cell Therapy Approaches for Immune Dysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome
Current Gene Therapy Canonical Wnt/Beta-Catenin Signaling Network as Emerging Signaling Cascade for Therapeutic Intervention in Chronic Renal Disease
Current Drug Targets Potential Utility of Telmisartan, an Angiotensin II Type 1 Receptor Blocker with Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ)-Modulating Activity for the Treatment of Cardiometabolic Disorders
Current Molecular Medicine Nephrotoxicity Associated with Antiretroviral Therapy in HIV-Infected Patients
Current Drug Safety A Novel Combined Pharmacophore Mapping and Quantitative Structure Selectivity Relationship Analysis for the Development of Potent and Selective Human Aldose Reductase Inhibitors
Current Computer-Aided Drug Design Therapeutic Implications of Superoxide Dismutase And Its Importance in Kinase Drug Discovery
Current Topics in Medicinal Chemistry Novel Sample Preparation for Mass Spectral Analysis of Complex Biological Samples
Current Proteomics Use of N-acetyl-cysteine to Prevent Nephrotoxicity Associated with Iodinated Contrast Agents
Current Drug Therapy Diagnostic Criteria for Metabolic Syndrome in Diet-Induced Rodent Models: A Systematic Review
Current Diabetes Reviews Herbal and Traditional Chinese Medicine for the Treatment of Cardiovascular Complications in Diabetes Mellitus
Current Diabetes Reviews