Potential Role Of Macrophages Research Articles

Macrophages in guided bone regeneration: potential roles and future directions.

Guided bone regeneration (GBR) is one of the most widely used and thoroughly documented alveolar bone augmentation surgeries. However, implanting GBR membranes inevitably triggers an immune response, which can lead to inflammation and failure of bone augmentation. It has been shown that GBR membranes may significantly improve in vivo outcomes as potent immunomodulators, rather than solely serving as traditional barriers. Macrophages play crucial roles in immune responses and participate in the entire process of bone injury repair. The significant diversity and high plasticity of macrophages complicate our understanding of the immunomodulatory mechanisms underlying GBR. This review provides a comprehensive summary of recent findings on the potential role of macrophages in GBR for bone defects in situ. Specifically, macrophages can promote osteogenesis or fibrous tissue formation in bone defects and degradation or fibrous encapsulation of membranes. Moreover, GBR membranes can influence the recruitment and polarization of macrophages. Therefore, immunomodulating GBR membranes are primarily developed by improving macrophage recruitment and aggregation as well as regulating macrophage polarization. However, certain challenges remain to be addressed in the future. For example, developing more rational and sophisticated sequential delivery systems for macrophage activation reagents; addressing the interference of bone graft materials and dental implants; and understanding the correlations among membrane degradation, macrophage responses, and bone regeneration.

Impact of photobiomodulation on macrophages and their polarization during diabetic wound healing: a systematic review.

This review aims to providing essential information and the current knowledge about the potential role of macrophages, especially their M2 subtypes in different diabetic wounds both in clinical and pre-clinical models under the influence of photobiomodulation (PBM). The long-term goal is to advance the macrophage-based therapies to accelerate healing of diabetic foot ulcers. We reviewed all databases provided by PubMed, Google Scholar, Scopus, Web of Science, and Cochrane precisely from their dates of inception to 25/10/2021. The keywords of Diabetes mellitus diseases, wound healing, macrophage, and photobiomodulation or low-level laser therapy were used in this systematic review.A total of 438 articles were initially identified in pubmed.ncbi.nlm.nih.gov (15 articles), Google scholar (398 articles), Scopus (18 articles), and Web of Science (7 articles). Four hundred sixteen articles that remained after duplicate studies (22 articles) were excluded. After screening abstracts and full texts, 14 articles were included in our analysis. Among them, 4 articles were about the effect of PBM on macrophages in type 2 diabetes and also found 10 articles about the impact of PBM on macrophages in type 1 diabetes. The obtained data from most of the reviewed studies affirmed that the PBM alone or combined with other agents (e.g., stem cells) could moderate the inflammatory response and accelerate the wound healing process in pre-clinical diabetic wound models. However, only very few studies conducted the detailed functions of polarized macrophages and M2 subtypes in wound healing of diabetic models under the influence of PBM. Further pre-clinical and clinical investigations are still needed to investigate the role of M2 macrophages, especially its M2c subtype, in the healing processes of diabetic foot ulcers in clinical and preclinical settings.

Targeting cystic fibrosis inflammation in the age of CFTR modulators: focus on macrophages.

Cystic fibrosis (CF) is a life-shortening, multi-organ, autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most prominent clinical manifestation in CF is the development of progressive lung disease characterised by an intense, chronic inflammatory airway response that culminates in respiratory failure and, ultimately, death. In recent years, a new class of therapeutics that have the potential to correct the underlying defect in CF, known as CFTR modulators, have revolutionised the field. Despite the exciting success of these drugs, their impact on airway inflammation, and its long-term consequences, remains undetermined. In addition, studies querying the absolute requirement for infection as a driver of CF inflammation have challenged the traditional consensus on CF pathogenesis, and also emphasise the need to prioritise complementary anti-inflammatory treatments in CF. Macrophages, often overlooked in CF research despite their integral role in other chronic inflammatory pathologies, have increasingly become recognised as key players in the initiation, perpetuation and resolution of CF lung inflammation, perhaps as a direct result of CFTR dysfunction. These findings suggest that macrophages may be an important target for novel anti-inflammatory interventional strategies to effectively treat CF lung function decline. This review will consider evidence for the efficacy of anti-inflammatory drugs in the treatment of CF, the potential role of macrophages, and the significance of targeting these pathways at a time when rectifying the basic defect in CF, through use of novel CFTR modulator therapies, is becoming increasingly viable.

Salt-sensitive blood pressure rise in type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation—a proof-of-concept study

Type 1 diabetes patients are more prone to have hypertension than healthy individuals, possibly mediated by increased blood pressure (BP) sensitivity to high salt intake. The classical concept proposes that the kidney is central in salt-mediated BP rises, by insufficient renal sodium excretion leading to extracellular fluid volume expansion. Recent animal-derived findings, however, propose a causal role for disturbance of macrophage-mediated lymphangiogenesis. Its relevance for humans, specifically type 1 diabetes patients, is unknown. The present study aimed to assess responses of type 1 diabetes patients to a dietary salt load with regard to BP, extracellular fluid volume (using precise iohexol measurements), and CD163+ macrophage and lymphatic capillary density in skin biopsies. Also, macrophage expression of HLA-DR (a proinflammatory marker) and CD206 (an anti-inflammatory marker) was assessed. Type 1 diabetes patients (n = 8) showed a salt-sensitive BP increase without extracellular fluid volume expansion. Whereas healthy controls (n = 12), who had no BP increase, showed increased skin CD163+ and HLA-DR+ macrophages and dilation of lymphatic skin vasculature after the dietary salt load, these changes were absent (and in case of HLA-DR more heterogenic) in type 1 diabetes patients. In conclusion, we show that salt sensitivity in type 1 diabetes patients cannot be explained by the classical concept of extracellular fluid volume expansion. Rather, we open up a potential role for macrophages and the lymphatic system. Future studies on hypertension and diabetes need to scrutinize these phenomena.

Role of hypochlorous acid (HOCl) and other inflammatory mediators in the induction of macrophage extracellular trap formation

The infiltration of activated leukocytes, including macrophages, at sites of inflammation and the formation and presence of hypochlorous acid (HOCl) are interlinked hallmarks of many debilitating disease processes, including atherosclerosis, arthritis, neurological and renal disease, diabetes and obesity. The production of extracellular traps by activated leukocytes in response to a range of inflammatory stimuli is increasingly recognised as an important process within a range of disease settings. We show that exposure of human monocyte-derived macrophages to pathophysiological levels of HOCl results in the dose-dependent extrusion of DNA and histones into the cellular supernatant, consistent with extracellular trap formation. Concurrent with, but independent of these findings, macrophage exposure to HOCl also resulted in an immediate and sustained cytosolic accumulation of Ca2+, culminating in the increased production of cytokines and chemokines. Polarisation of the macrophages prior to HOCl exposure revealed a greater propensity for inflammatory M1 macrophages to produce extracellular traps, whereas alternatively-activated M2 macrophages were less susceptible to HOCl insult. M1 macrophages also produced extracellular traps on exposure to phorbol myristate acetate (PMA), interleukin-8 (IL-8) and tumour necrosis factor α (TNFα). Taken together, these data indicate a potential role for macrophages in mediating extracellular trap formation, which may be relevant in pathological conditions characterised by chronic inflammation or excessive HOCl formation.

Carcinoembryonic antigen as a marker of radioresistance in colorectal cancer: a potential role of macrophages

BackgroundWe sought to identify the carcinoembryonic antigen (CEA) as a marker of radioresistance in rectal cancer.MethodsFrom July 1997 to January 2008, 104 patients with stage II or III rectal cancer who were treated with post-operative radiotherapy (PORT) were included in this study. The doses of radiotherapy ranged from 45 to 54.6 Gy. The CEA levels were measured before surgery. We analyzed the actuarial rates of overall survival (OS), distant metastasis (DM), and local recurrence (LR) using Kaplan-Meier curves. Multivariate analyses were performed with Cox regression models. We used THP-1 monocyte cell lines for macrophage differentiation (M0, M1 or M2). The RNA extracted from the macrophages was analyzed via a genomic method in the core laboratory. The radiosensitivities of CEA-rich LS1034 cells were compared between cells with and without the conditioned media from CEA-stimulated macrophages.ResultsPreoperative CEA levels ≥10 ng/mL were independent predictive factors for OS (p = 0.005), DM (p = 0.026), and LR (p = 0.004). The OS rates among the patients with pretreatment CEA levels < 10 ng/mL and ≥10 ng/mL were 64.5% and 35.9% (p = 0.004), respectively. The corresponding rates of DM were 40.6% and 73.1% (p = 0.024). The corresponding rates of LR were 6.6% and 33.9% (p = 0.002). In the M0 macrophages, exogenous CEA elicited a dose-response relationship with M2 differentiation. In the CEA-stimulated M0 cells, some mRNAs were upregulated by as much as 5-fold, including MMP12, GDF15, and JAG1. In the CEA-stimulated M2 cells, a 4-fold up-regulation of GADD45G mRNA was noted. The conditioned media from the CEA-stimulated M2 cells elicited an increase in the numbers of LS180, SW620, and LS1034 cells after irradiation. CEA caused the M2 differentiation of the macrophages.ConclusionPretreatment CEA levels ≥10 ng/mL are a significant risk factor for OS, DM, and LR following PORT for rectal cancer. CEA causes radioresistance in the presence of M2 macrophages. More comprehensive examinations prior to surgery and intensive adjuvant therapy are suggested for patients with CEA levels ≥10 ng/mL. Further studies of these mechanisms are needed.

Essential involvement of the CX3CL1-CX3CR1 axis in bleomycin-induced pulmonary fibrosis via regulation of fibrocyte and M2 macrophage migration

The potential role of macrophages in pulmonary fibrosis (PF) prompted us to evaluate the roles of CX3CR1, a chemokine receptor abundantly expressed in macrophages during bleomycin (BLM)-induced PF. Intratracheal BLM injection induced infiltration of leukocytes such as macrophages into the lungs, which eventually resulted in fibrosis. CX3CR1 expression was mainly detected in the majority of macrophages and in a small portion of α-smooth muscle actin-positive cells in the lungs, while CX3CL1 was expressed in macrophages. BLM-induced fibrotic changes in the lungs were reduced without any changes in the number of leukocytes in Cx3cr1−/− mice, as compared with those in the wild-type (WT) mice. However, intrapulmonary CX3CR1+ macrophages displayed pro-fibrotic M2 phenotypes; lack of CX3CR1 skewed their phenotypes toward M1 in BLM-challenged lungs. Moreover, fibrocytes expressed CX3CR1, and were increased in BLM-challenged WT lungs. The number of intrapulmonary fibrocytes was decreased in Cx3cr1−/− mice. Thus, locally-produced CX3CL1 can promote PF development primarily by attracting CX3CR1-expressing M2 macrophages and fibrocytes into the lungs.

Alternative Anaphylactic Routes: The Potential Role of Macrophages.

Anaphylaxis is an acute, life-threatening, multisystem syndrome resulting from the sudden release of mediators from effector cells. There are two potential pathways for anaphylaxis. The first one, IgE-dependent anaphylaxis, is induced by antigen (Ag) cross-linking of Ag-specific IgE bound to the high-affinity IgE receptor (FcεRI) on mast cells and basophils. The second one, IgG-dependent anaphylaxis is induced by Ag cross-linking of Ag-specific IgG bound to IgG receptors (FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, and FcγRIIIA) on macrophages, neutrophils, and basophils. Macrophages exhibit a huge functional plasticity and are capable of exerting their scavenging, bactericidal, and regulatory functions under a wide variety of tissue conditions. Herein, we will review their potential role in the triggering and development of anaphylaxis. Thereby, macrophages, among other immune cells, play a role in both anaphylactic pathways (1) by responding to anaphylactic mediators secreted by mast cells after specific IgE cross-linking or (2) by acting as effector cells in the anaphylactic response mediated by IgG. In this review, we will go over the cellular and molecular mechanisms that take place in the above-mentioned anaphylactic pathways and will discuss the clinical implications in human allergic reactions.

Novel Identification of LYVE-1 Positive Macrophages in Rheumatoid Synovial Tissue

Objective: LYVE-1+ macrophages are observed in a range of cancers, where they play a role in tumour lymphangiogenesis. In rheumatoid arthritis (RA), lymphangiogenesis increases in the early stage of the disease and decreases as it progresses, potentially exacerbating inflammatory cell persistence. We investigated whether LYVE-1+ macrophages were present in RA synovium. Methods: Synovial tissue from RA patients was obtained at joint replacement surgery and immunohistochemistry was performed to visualise LYVE-1+ and CD68+ cells. Results: LYVE-1+ macrophages were present in rheumatoid synovial tissue, the first observation of this kind. Conclusion: Despite the reduction in lymphangiogenesis in chronic RA, LYVE-1 positive macrophages are present and there is a potential role for macrophages in the generation of lymphatic vessels.

Adipose Tissue Macrophages (ATM) of obese patients are releasing increased levels of prolactin during an inflammatory challenge: A role for prolactin in diabesity?

BackgroundObesity, characterized by low grade inflammation, induces adipose tissue macrophage (ATM) infiltration in white adipose tissue (AT) in both humans and rodents, thus contributing to insulin resistance. Previous studies have shown altered prolactin secretion in obesity, however, studies linking ATM infiltration and prolactin (PRL) secretion to the pathogenesis of the metabolic syndrome, obesity and diabetes are lacking. Methods/ResultsIn vivo, qPCR and Western blot analysis demonstrated that prolactin expression was increased in AT of obese rats and also in human AT from obese, obese pre-diabetic and obese diabetic compared to lean counterparts. Immunohistochemistry of obese rat and human AT sections demonstrated a specific expression of prolactin in macrophages. In vitro, we demonstrated that hyperglycemia and inflammation stimulated macrophages (human THP-1 cell line and sorted rat ATM) to express PRL, when challenged with different glucose concentrations with or without IL1β. In in vivo and in vitro experiments, we assessed the expression of Pit-1 (PRL-specific transcription factor) and found that its expression was parallel to PRL expression. ConclusionsIn this study, we show that rodent and human macrophages synthesize prolactin in response to inflammation and high glucose concentrations. General significanceOur data shed new light on the potential role of macrophages in the physiopathology of diabesity via the PRL expression and on its expression mechanism and regulation.

Contribution of Macrophages to Enhanced Regenerative Capacity of Dorsal Root Ganglia Sensory Neurons by Conditioning Injury

Although the central branches of the dorsal root ganglion (DRG) sensory neurons do not spontaneously regenerate, a conditioning peripheral injury can promote their regeneration. A potential role of macrophages in axonal regeneration was proposed, but it has not been critically addressed whether macrophages play an essential role in the conditioning injury model. After sciatic nerve injury (SNI) in rats, the number of macrophages in DRGs gradually increased by day 7. The increase persisted up to 28 d and was accompanied by upregulation of inflammatory mediators, including oncomodulin. A macrophage deactivator, minocycline, reduced the macrophage number and expressions of the inflammatory mediators. Molecular signatures of conditioning effects were abrogated by minocycline, and enhanced regenerative capacity was substantially attenuated both in vitro and in vivo. Delayed minocycline infusion abrogated the SNI-induced long-lasting heightened neurite outgrowth potential, indicating a role for macrophages in the maintenance of regenerative capacity. Intraganglionic cAMP injection also resulted in an increase in macrophages, and minocycline abolished the cAMP effect on neurite outgrowth. However, conditioned media (CM) from macrophages treated with cAMP did not exhibit neurite growth-promoting activity. In contrast, CM from neuron-macrophage cocultures treated with cAMP promoted neurite outgrowth greatly, highlighting a requirement for neuron-macrophage interactions for the induction of a proregenerative macrophage phenotype. The growth-promoting activity in the CM was profoundly attenuated by an oncomodulin neutralizing antibody. These results suggest that the neuron-macrophage interactions involved in eliciting a proregenerative phenotype in macrophages may be a novel target to induce long-lasting regenerative processes after axonal injuries in the CNS.

A potential role for macrophages in maintaining lipopolysaccharide-induced subacute airway inflammation in rats

Bacterial infection is a key factor in airway inflammation. The present study describes the time-dependent changes in the leukocyte counts and cytokine levels of the bronchoalveolar lavage fluid (BALF) following subacute airway inflammation induced by lipopolysaccharide (LPS), a major component of the outer membranes of Gram-negative bacteria. LPS (200 μg/rat) or saline was intratracheally administered to rats which were sacrificed 2, 4 or 7 days after LPS treatment. Airway inflammation was evaluated using hematoxylin and eosin staining, cell counts and proinflammatory cytokine levels in the BALF. Rat airways obtained from the LPS group exhibited marked airway wall thickening and infiltration of inflammatory cells compared with the control group, as well as elevated cell counts (neutrophils, macrophages, lymphocytes) and proinflammatory cytokine levels [(tumor necrosis factor (TNF)-α, interleukin (IL)-1β, cytokine-induced neutrophil chemoattractant (CINC)-1)] in the BALF, which peaked on day 2 and subsequently decreased until the experimental endpoint. Notably, IL-1β levels induced by LPS changed in a similar manner to macrophage cell counts, but not neutrophil and lymphocyte counts. Moreover, TNF-α and CINC-1 levels did not decrease as rapidly as neutrophil counts after peaking. These findings suggest that macrophages may play a significant role in maintaining subacute inflammatory responses induced by LPS in rat airways.

Decidual macrophages are significantly increased in spontaneous miscarriages and over-express FasL: a potential role for macrophages in trophoblast apoptosis.

Decidual macrophages (DM) are the second most abundant population in the fetal-maternal interface. Their role has been so far identified as being local immuno-modulators favoring the maternal tolerance to the fetus. Herein we investigated tissue samples from 11 cases of spontaneous miscarriages and from 9 cases of elective terminations of pregnancy. Using immunohistochemistry and dual immunofluorescence we have demonstrated that in spontaneous miscarriages the DM are significantly increased. Additionally, we noted a significant up-regulation of macrophage FasL expression. Our results further support a dual role for DM during pregnancy and miscarriages. We hypothesize that the baseline DM population in normal pregnancy is in line with an M2 phenotype supporting the ongoing gestation. In contrast, during spontaneous miscarriages, the increased FasL-expressing population could be a part of an M1 phenotype participating in Fas/FasL-related apoptosis. Our results highlight a new aspect of macrophage biology in pregnancy physiology and pathophysiology. Further studies with larger samples are needed to verify the current results and evaluate their clinical impact.

Potential role of macrophages as immunoregulators of pregnancy

The role of the maternal immune system during pregnancy has focused mainly on the aspect of immune tolerance to the invading trophoblast and, therefore, fetus. While this is a critical aspect of reproductive immunology, it is also important to consider the function of the maternal immune system in the promotion of implantation and maintenance of pregnancy. Apoptosis or cell death is not the final stage in tissue development. The quick and effective removal of apoptotic cells by tissue macrophages represents a vital process preventing "leak" of self-antigens and promoting the production of proliferative/survival factors. One of the key requirements of apoptotic cell clearance is the resolution of inflammatory conditions, which, as in the case of pregnancy, may have lethal consequences. This review will focus on decidual macrophages and their role on apoptosis and cell clearance during pregnancy.

The Role of the Immune System in Conjunctival Wound Healing After Glaucoma Surgery

The immune system has a fundamental role in the development and regulation of ocular healing, which plays an important role in the pathogenesis of most blinding diseases. This review discusses the mechanisms of normal wound healing, describing the animal and fetal wound healing models used to provide further insight into normal wound repair. In particular, conjunctival wound repair after glaucoma filtration surgery will be used to illustrate the contributions that the different components of the immune system make to the healing process. The potential role of macrophages, the possible regulatory effect of lymphocytes, and the important role of growth factors and cytokines in the wound healing reaction are discussed. The significance of the immune system in the pathogenesis of aggressive conjunctival scarring is addressed, particularly assessing the predisposing factors, including drugs, age, and ethnicity. The rationale behind the pharmacological agents currently used to modulate the wound healing response and the effects these drugs have on the function of the immune system are described. Finally, potential new therapeutic approaches to regulating the wound healing response are reported.

Macrophages and inflammatory mediators in tissue injury.

Tissue injury induced by a diverse group of xenobiotics appears to involve both direct and indirect damage to target cells. Thus, while chemicals may act directly on target cells resulting in toxicity, they may also act indirectly by recruiting and activating resident and inflammatory tissue macrophages. Macrophages are potent secretory cells that release an array of mediators, including proinflammatory and cytotoxic cytokines and growth factors, bioactive lipids, hydrolytic enzymes, reactive oxygen intermediates, and nitric oxide--each of which has been implicated in the pathogenesis of tissue injury. The potential role of macrophages and their mediators in tissue injury has been extensively investigated in the lung and the liver. In both of these tissues, xenobiotics induce localized macrophage accumulation and mediator release. Furthermore, when macrophage functioning is blocked, pulmonary and hepatic injury-induced agents such as ozone, bleomycin, acetaminophen, carbon tetrachloride, and galactosamine are reduced. These data provide direct support for the hypothesis that macrophages and the mediators they release contribute to xenobiotic-induced tissue injury.

Effect of treatment with methylprednisolone on duration of pseudopregnancy and on macrophages and T lymphocytes in rabbit corpora lutea.

The potential role of macrophages and T lymphocytes in the destruction of the corpus luteum at the end of the luteal phase was investigated by treating pseudopregnant rabbits with the immunosuppressant glucocorticoid methylprednisolone. Eleven specific pathogen-free New Zealand White rabbits were injected with pregnant mares' serum gonadotrophin (40 iu, i.m.), followed 2 days later by human chorionic gonadotrophin (40 iu, i.v.) to stimulate ovulation. The following day (day 1 of pseudo-pregnancy) all animals had an oestradiol-filled Silastic capsule implanted s.c., to ensure that oestradiol, the luteotrophic hormone in this species, would not be limiting. From day 10 of pseudopregnancy, three animals were injected with a low dose of methylprednisolone (2 mg kg-1 per day) until day 20. Three other animals were injected with a higher dose of methylprednisolone (20 mg kg-1 per day) from day 13 of pseudopregnancy until day 19. Five animals served as control, vehicle-injected animals. Blood samples were taken at intervals and assayed for progesterone. Immunofluorescence was used to stain luteal tissue for macrophages, T lymphocytes and class II antigens, and positive cells were counted under high-power magnification. Methylprednisolone treatment reduced (by about 70%), but did not eliminate, the macrophages in the regressing corpora lutea. In contrast, the high dose of methylprednisolone essentially eliminated T lymphocytes, and reduced (by about 90%) the number of cells expressing class II antigen in the luteal tissue. Despite the effects of methylprednisolone on these cells, serum progesterone profiles were not altered by treatment with methylprednisolone, and pseudopregnancy was of normal duration.(ABSTRACT TRUNCATED AT 250 WORDS)

The contribution of alveolar macrophages to hyperreactive airway disease

Thus, there is substantial evidence that favors a role for macrophages in subjects with atopic asthma. The precise manner in which these cells participate and the relative degree to which these cells contribute to, or orchestrate, events remains to be delineated. Research on the potential role of macrophages in asthma syndromes remains in its infancy. In time we will discover new roles for mononuclear phagocytederived mediators and many more new mediators that will play a role in the complex immunologic events ongoing in the airways of patients with asthma. Also, future research will continue to explore what promises to be a productive area of research, namely, cell-cell interactions and the manner in which many cells participate together in the pathophysiology of asthma. If macrophages can be demonstrated to influence airway inflammation associated with atopic disease, they may be appropriate targets for therapeutic intervention.