Macrophage Dysfunction Research Articles

Macrophage S1PR2 Drives Sepsis-induced Immunosuppression by Exacerbating Mitochondrial Fragmentation.

Macrophage mitochondrial dysfunction is associated with immunosuppression and poor prognosis of septic patients. Mitochondrial fragmentation drives mitochondrial dysfunction. Our previous study has found that S1PR2 regulates macrophage phagocytosis during sepsis, while the role of S1PR2 in immunosuppression and the mechanisms remain further studied. This study aimed to unveil the relationship between macrophage mitochondrial fragmentation and sepsis-induced immunosuppression, as well as the S1PR2-related mechanisms thereof. Peripheral blood monocytes were collected from healthy controls (n = 12), nonseptic critical controls (n = 13) and septic patients (n = 19). Peritoneal macrophages were harvested from wildtype and S1pr2-/- mice (MMRRC strain iD, 12830) after cecal ligation and puncture (CLP). Mitochondrial ultrastructure was evaluated using transmission electron microscopy. The impact of mitochondrial ultrastructure alteration on immunosuppression of monocytes-macrophages was evaluated. Compared with nonseptic and healthy controls, peripheral blood monocytes from septic patients exhibited increased S1PR2 expression, mitochondrial fragmentation, and mitochondrial dysfunction. Mitochondrial fragmentation was negatively associated with HLA-DR expression. S1PR2 expression was positively correlated with mitochondrial fragmentation and negatively correlated with HLA-DR expression. In mice subjected to CLP, S1PR2 depletion ameliorated macrophage mitochondrial fragmentation and dysfunction, boosted immunity, and improved survival. Mechanistically, in response to sepsis, S1PR2 activates ROCK I to induce Drp1 phosphorylation, resulting in Drp1-dependent mitochondrial fragmentation of macrophages. Drp1 inhibition by Mdivi-1 mitigated S1PR2-induced macrophage immunosuppression and improved the prognosis of mice following CLP. In conclusion, S1PR2-induced mitochondrial fragmentation is a crucial factor mediating septic immunosuppression, highlighting its potential as a promising therapeutic target in sepsis.

536 Sodium butyrate promotes healing of diabetic wounds through modulation of the epigenome in dysfunctional macrophages

536 Sodium butyrate promotes healing of diabetic wounds through modulation of the epigenome in dysfunctional macrophages

Severity and prognosis of COVID-19 complicated by autoimmune pulmonary alveolar proteinosis

BackgroundThe prognosis of patients with coronavirus disease 2019 (COVID-19) was poor although its survival rate has been improved after the occurrence of the Omicron strain. Autoimmune pulmonary alveolar proteinosis (APAP), a lung disease caused by macrophage dysfunction induced by anti-granulocyte-macrophage colony-stimulating factor (GM–CSF)–neutralizing autoantibodies, is characterized by the deposition of proteinaceous material in the alveolar spaces. The clinical course of COVID-19 in patients with APAP remains unclear and this study aimed to clarify it. MethodsThe data of 23 patients with APAP, who were diagnosed with COVID-19 between January 2020 and May 2023 and collected through a nationwide questionnaire surveillance system, were retrospectively reviewed. ResultsBased on the epidemiological frequency at disease onset, suspected strains of severe acute respiratory syndrome coronavirus 2 were Omicron (n = 18) and non-Omicron (n = 5). Fifteen patients were vaccinated. Six and three patients received anti-viral drugs and corticosteroids, respectively. One patient in the third trimester of pregnancy died despite treatment in the intensive care unit. Six patients were complicated by pneumonia and/or required supplemental oxygen. These patients were suspected to have non-Omicron strains (p = 0.087). Vaccination status showed a significant association with suspected Omicron strains. The radiological findings in four patients and shortness of breath improved in two of the four patients after COVID-19. ConclusionsThe severity and prognosis of the patients were not worse than those predicted based on the results of a previous study. The transition from a non-Omicron strain to an Omicron strain and the vaccination status may have affected these results.

The role of macrophage and adipocyte mitochondrial dysfunction in the pathogenesis of obesity.

Obesity has emerged as a prominent global public health concern, leading to the development of numerous metabolic disorders such as cardiovascular diseases, type-2 diabetes mellitus (T2DM), sleep apnea and several system diseases. It is widely recognized that obesity is characterized by a state of inflammation, with immune cells-particularly macrophages-playing a significant role in its pathogenesis through the production of inflammatory cytokines and activation of corresponding pathways. In addition to their immune functions, macrophages have also been implicated in lipogenesis. Additionally, the mitochondrial disorders existed in macrophages commonly, leading to decreased heat production. Meantime, adipocytes have mitochondrial dysfunction and damage which affect thermogenesis and insulin resistance. Therefore, enhancing our comprehension of the role of macrophages and mitochondrial dysfunction in both macrophages and adipose tissue will facilitate the identification of potential therapeutic targets for addressing this condition.

ENaC contributes to macrophage dysfunction in cystic fibrosis.

Cystic fibrosis (CF) is a chronic systemic disease caused by dysfunctional or absent cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is expressed in human immune cells and plays a role in regulating innate immunity both directly and indirectly. Besides CFTR, research indicates that the epithelial sodium channel (ENaC) also contributes to dysfunction in CF airway epithelial cells. However, the impact of non-CFTR ion channel dysfunction on CF immune responses is not yet fully understood. A precise understanding of how CF immune function is regulated by ion channels may allow antibiotic-and mutation-agnostic treatment approaches to chronic bacterial infection and inflammation. Therefore, we hypothesized that ENaC is aberrantly expressed in CF macrophages and directly contributes to impaired phagocytic and inflammatory functions. ENaC expression was characterized in human immune cells isolated from CF and non-CF blood donors. Monocyte-derived macrophage (MDM) function and bacterial killing was tested in the setting of ENaC modulation. Baseline expression of ENaC in human CF MDMs, lymphocytes, and granulocytes was increased at both the transcript and protein level relative to non-CF controls and persisted after exposure to bacteria. Inhibition of CFTR in non-CF MDMs resulted in ENaC overexpression.CFTR modulator treatment reduced but did not eliminate ENaC overexpression in CF MDMs. Interestingly, ENaC inhibition with Amiloride increased CFTR expression. Amiloride-treated CF MDMs also showed normalized ROS production, improved autophagy, and decreased pro-inflammatory cytokine production. Finally, results from an ion channel microarray indicated that sodium channel expression in CF MDMs normalized after Amiloride treatment with minimal effect on other ion channels. ENaC is overexpressed in CF immune cells and is associated with abnormal macrophage function. ENaC modulation in immune cells is a novel potential therapeutic target for infection control in CF, either in combination with CFTR modulators, or as a sole agent for patients not currently eligible for CFTR modulators.

Hematopoietic NADPH Oxidase 4 Prevents Atherogenesis by Inhibiting High Calorie Diet-Induced Monocyte Priming and the Overrecruitment of Dysfunctional Monocyte-Derived Macrophages

Hematopoietic NADPH Oxidase 4 Prevents Atherogenesis by Inhibiting High Calorie Diet-Induced Monocyte Priming and the Overrecruitment of Dysfunctional Monocyte-Derived Macrophages

Whole Lung Lavage in Autoimmune Pulmonary Alveolar Proteinosis: Unique Challenges in a Resource-Limited Setting.

Autoimmune pulmonary alveolar proteinosis (PAP) is characterized by antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF), alveolar macrophage dysfunction, and surfactant accumulation. Whole lung lavage (WLL) is the treatment of choice in patients with PAP and severe hypoxemia. In resource-limited settings, WLL can be performed in the intubated, anesthetized patient who is being one lung ventilated using a Y-type bladder irrigation catheter for saline instillation and drainage.

Race for the surface between THP-1 macrophages and Staphylococcus aureus on various titanium implants with well-defined topography and wettability.

Gristina et al. (1987) suggested the fate of a biomaterial is decided in a “race for the surface” between pathogens and the host. To gain deeper insight into the mechanisms behind this concept, we investigated the “race for the surface” across three co-culture scenarios with THP-1 macrophages and Staphylococcus aureus (1:1 ratio), varying the order of addition: (i) simultaneous, (ii) macrophages first, and (iii) S. aureus first, on six Ti6Al4V-ELI surfaces modified with specific topographies and wettability. The outcome of the race for the surface was not influenced by these biomaterials but by the chronological introduction of macrophages and S. aureus. When macrophages and S. aureus arrived simultaneously, macrophages won the race, leading to the lowest number of viable S. aureus through rapid phagocytosis and killing. When macrophages arrived and established first, macrophages still prevailed but under greater challenge resulting from the lower bacterial killing efficiency of adherent macrophages and numerous viable intracellular bacteria, supporting the concept of the so-called immunocompromised zone around implants (upregulation of TLR-2 receptor and pro-inflammatory IL-1β). When S. aureus arrived first establishing a biofilm, bacteria won the race, leading to macrophage dysfunction and cell death (upregulation of FcγR and TLR-2 receptors, NF-κB signaling, NOX2 mediated reactive oxygen species), contributing to a persistent biofilm phenotype (upregulation of clfA, icaA, sarA, downregulation of agrA, hld, lukAB) and intracellular survival of S. aureus (lipA upregulation). The clinical implications are bacterial colonization of the implant and persistence of intracellular bacteria in periprosthetic tissues, which can lead to infection chronicity. Statement of SignificanceGristina et al. (1987) suggested the fate of a biomaterial is decided in a “race for the surface” between bacterial pathogens and host cells. There is a lack of in vitro co-culture models and knowledge on macrophage-S. aureus interactions on biomaterial surfaces, and none has evaluated the expression of virulence factors in S. aureus biofilms.We have successfully developed co-culture models and molecular panels and elucidated important cellular and molecular interactions between macrophages and S. aureus on a broad range of titanium biomaterials with well-defined surface topography and wettability. Our findings highlight the critical role of biofilm formation and the chronological order of bacteria or macrophage arrival in determining the fate of the surface.

Mechanical Force on Hydrogel Implication on Enhanced Drug Release, Antibacterial, and M2 Macrophage Polarization: New Insights Alleviate Diabetic Wound Healing.

Diabetic foot ulcers/chronic wounds are difficult to treat because of dysfunctional macrophage response and decreased phenotype transition from the M1 to M2 status. This causes severe inflammation, less angiogenesis, microbial infections, and small deformation in wound beds, affecting the healing process. The commercial wound dressing material has limited efficacy, poor mechanical strength, extra pain, and new granulated tissue formed in a mesh of gauze. It is desired to create tough, skin-adhesive, antifouling, sustainable M2 phenotype-enabling, and mechanoresponsive drug-releasing hydrogel. To resolve this, zwitterionic poly(sulfobetaine methacrylate) (SB) incorporated with keratin-exfoliated MoS2 and bee-wax nanoparticles were developed to deliver phenytoin upon application of mechanical forces. Human hair keratin was used for exfoliation of MoS2, and bee-wax nanoparticles loaded with phenytoin were used as cross-linkers of SB hydrogel. The cross-linked SB-MO15-B hydrogel has high mechanical properties, with more tensile strength and strain of 118 kPa and 1485%. Under external mechanical force, hydrogel deformed to release phenytoin of 38% (tensile) and 24% (compressive), which was higher compared to static condition (12%). The penetration of phenytoin into skin tissue was also improved by the mechanical force applied to the hydrogel. SB-MO15-B hydrogel effectively activates the polarization of macrophages toward the M2 phenotype, promotes cell proliferation, and also shows superior antibacterial properties. In vivo results demonstrate that hydrogel rapidly promotes diabetic wound repair through fast antiinflammation and M2 macrophage polarization. Therefore, a robust mechanoresponsive hydrogel would provide a new strategy to deliver the drug and also tune the M2 macrophage polarization for chronic wound healing.

Macrophages and the microbiome in chronic obstructive pulmonary disease.

COPD is a heterogeneous disease of the lungs characterised by restricted airflow. Chronic inflammation and recurrent bacterial infections are known to be important driving factors in exacerbations of this disease. Despite a marked increase in the number of alveolar macrophages present in the lungs of COPD patients, there is evidence of reduced clearance of pathogenic bacteria, leading to recurrent infection, exacerbation and subsequent lung function decline. This is thought to be attributed to a defect in the phagocytic capability of both alveolar and monocyte-derived macrophages in COPD. In addition to this defect, there is apparent selectivity in bacterial uptake by COPD macrophages because certain pathogenic genera, such as Haemophilus, Moraxella and Streptococcus, are taken up more readily than others. The respiratory microbiome plays a key role in regulating the host immune response both in health and during chronic inflammation. In patients with COPD, there are distinct changes in the composition of the respiratory microbiome, particularly the lower respiratory tract, where dominance of clinically relevant pathogenic species is commonly observed. Whether there are links between these changes in the microbiome and dysfunctional macrophage phagocytosis has not yet been widely studied. This review aims to discuss what is currently known about these phenomena and to explore interactions between macrophages and the respiratory microbiome.

Targeting delivery of mifepristone to endometrial dysfunctional macrophages for endometriosis therapy

Endometriosis seriously affects 6–10 % of reproductive women globally and poses significant clinical challenges. The process of ectopic endometrial cell colonization shares similarities with cancer, and a dysfunctional immune microenvironment, characterized by non-classically polarized macrophages, plays a critical role in the progression of endometriosis. In this study, a targeted nano delivery system (BSA@Mif NPs) was developed using bovine serum albumin (BSA) as the carrier of mifepristone. The BSA@Mif NPs were utilized to selectively target M2 macrophages highly enriched in ectopic endometrial tissue via the SPARC receptor. This targeting strategy increases drug concentration at ectopic lesions while minimizing its distribution to normal tissue, thereby reducing side effects. In vitro studies demonstrated that BSA@Mif NPs not only enhanced the cellular uptake of M2-type macrophages and ectopic endometrial cells but also improved the cytotoxic effect of mifepristone on ectopic endometrial cells. Furthermore, the BSA@Mif NPs effectively induced immunogenic cell death (ICD) in ectopic endometrial cells and repolarized M2-type macrophages toward the M1 phenotype, resulting in a synergistic inhibition of ectopic endometrial cell growth. In vivo experiments revealed that BSA@Mif NPs exhibited significant therapeutic efficacy in endometriosis-bearing mice by increasing drug accumulation in the endometriotic tissues and modulating the immune microenvironment. This targeted biomimetic delivery strategy presents a promising approach for the development of endometriosis-specific therapies based on existing drugs. Statement of significanceMacrophages play an essential role in immune dysfunctional microenvironment promoting the occurrence and progression of endometriosis and can be a crucial target for developing immune microenvironment regulation strategies for the unmet long-term management of endometriosis. The albumin nanoparticles constructed based on SPARC overexpression in macrophages and endometrial cells and albumin biosafety can achieve the targeted therapy of endometriosis by increasing the passive- and active-mediated drug accumulation in ectopic endometrium and remodeling the immune microenvironment based on macrophage regulation. This study has the following implications: i) overcoming the inherent shortcomings of clinical drugs by nanotechnology is an alternative way of developing medication; ii) developing microenvironment modulation strategies based on macrophage regulation for endometriosis management is feasible.

Cross-Species Studies Reveal That Dysregulated Mitochondrial Gene Expression and Electron Transport Complex I Activity Are Crucial for Sarcopenia

The significance of complex I of the electron transport chain (ETC) in the aging process is widely acknowledged; however, its specific impact on the development of sarcopenia in muscle remains poorly understood. This study elucidated the correlation between complex I inhibition and sarcopenia by conducting a comparative analysis of skeletal muscle gene expression in sarcopenia phenotypes from rats, mice, and humans. Our findings reveal a common mechanistic link across species, particularly highlighting the correlation between the suppression of complex I of ETC activity and dysregulated mitochondrial transcription and translation in sarcopenia phenotypes. Additionally, we observed macrophage dysfunction alongside abnormal metabolic processes within skeletal muscle tissues across all species, implicating their pathogenic role in the onset of sarcopenia. These discoveries underscore the importance of understanding the shared mechanisms associated with complex I of ETC in sarcopenia development. The identified correlations provide valuable insights into potential targets for therapeutic interventions aimed at mitigating the impact of sarcopenia, a condition with substantial implications for aging populations.

Engineered Enucleated Mesenchymal Stem Cells Regulating Immune Microenvironment and Promoting Wound Healing.

Persistent excessive inflammation caused by neutrophil and macrophage dysfunction in the wound bed leads to refractory response during wound healing. However, previous studies using cytokines or drugs often suffer from short half-lives and limited targeting, resulting in unsatisfactory therapeutic effects. Herein, the enucleated mesenchymal stem cell is engineered by aptamer bioorthogonal chemistry to modify the cell membrane and mRNA loading in the cell cytoplasm as a novel delivery vector (Cargocyte) with accurate targeting and sustained cytokine secretion. Cargocytes can successfully reduce NETosis by targeting the nuclear chromatin protein DEK protein with aptamers and sustaining interleukin (IL)-4 expression to overcome the challenges associated with the high cost and short half-life of IL-4 protein and significantly prevent the transition of macrophages into the M1 phenotype. Therapeutic effects have been demonstrated in murine and porcine wound models and have powerful potential to improve wound immune microenvironments effectively. Overall, the use of engineered enucleated mesenchymal stem cells as a delivery system may be a promising approach for wound healing.

IKKα-STAT3-S727 axis: a novel mechanism in DOX-induced cardiomyopathy

Doxorubicin (DOX) is an effective chemotherapeutic drug, but its use can lead to cardiomyopathy, which is the leading cause of mortality among cancer patients. Macrophages play a role in DOX-induced cardiomyopathy (DCM), but the mechanisms undlerlying this relationship remain unclear. This study aimed to investigate how IKKα regulates macrophage activation and contributes to DCM in a mouse model. Specifically, the role of macrophage IKKα was evaluated in macrophage-specific IKKα knockout mice that received DOX injections. The findings revealed increased expression of IKKα in heart tissues after DOX administration. In mice lacking macrophage IKKα, myocardial injury, ventricular remodeling, inflammation, and proinflammatory macrophage activation worsened in response to DOX administration. Bone marrow transplant studies confirmed that IKKα deficiency exacerbated cardiac dysfunction. Macrophage IKKα knockout also led to mitochondrial damage and metabolic dysfunction in macrophages, thereby resulting in increased cardiomyocyte injury and oxidative stress. Single-cell sequencing analysis revealed that IKKα directly binds to STAT3, leading to the activation of STAT3 phosphorylation at S727. Interestingly, the inhibition of STAT3-S727 phosphorylation suppressed both DCM and cardiomyocyte injury. In conclusion, the IKKα-STAT3-S727 signaling pathway was found to play a crucial role in DOX-induced cardiomyopathy. Targeting this pathway could be a promising therapeutic strategy for treating DOX-related heart failure.

Effects of injury size on local and systemic immune cell dynamics in volumetric muscle loss.

We took a systems approach to the analysis of macrophage phenotype in regenerative and fibrotic volumetric muscle loss outcomes in mice together with analysis of systemic inflammation and of other leukocytes in the muscle, spleen, and bone marrow. Macrophage dysfunction in the fibrotic group occurred as early as day 1, persisted to at least day 28, and was associated with increased numbers of leukocytes in the muscle and bone marrow, increased pro-inflammatory marker expression in splenic macrophages, and changes in the levels of pro-inflammatory cytokines in the blood. The most prominent differences were in muscle neutrophils, which were much more abundant in fibrotic outcomes compared to regenerative outcomes at day 1 after injury. However, neutrophil depletion had little to no effect on macrophage phenotype or on muscle repair outcomes. Together, these results suggest that the entire system of immune cell interactions must be considered to improve muscle repair outcomes.

MSR1-dependent efferocytosis improved ischemia-reperfusion injury following aged-donor liver transplantation in mice by regulating the pro-resolving polarisation of macrophages

Compared with young liver donors, aged liver donors are more susceptible to ischemia-reperfusion injury (IRI) following transplantation, which may be related to excessive inflammatory response and macrophage dysfunction, but the specific mechanism is unclear. Macrophage scavenger receptor 1 (MSR1) is a member of the scavenger receptor family, and plays an important regulatory role in inflammation response and macrophage function regulation. But its role in IRI following aged-donor liver transplantation is still unclear. This study demonstrates that MSR1 expression is decreased in macrophages from aged donor livers, inhibiting their efferocytosis and pro-resolving polarisation. Decreased MSR1 is responsible for the more severe IRI suffered by aged donor livers. Overexpression of MSR1 using F4/80-labelled AAV9 improved intrahepatic macrophage efferocytosis and promoted pro-resolving polarisation, ultimately ameliorating IRI following aged-donor liver transplantation. In vitro co-culture experiments further showed that overexpression of MSR1 promoted an increase in calcium concentration, which further activated the PI3K-AKT-GSK3β pathway, and induced the upregulation of β-catenin. Overall, MSR1-dependent efferocytosis promoted the pro-resolving polarisation of macrophages through the PI3K-AKT-GSK3β pathway-induced up-regulating of β-catenin leading to improved IRI following aged-donor liver transplantation.

M2 macrophage-polarized anti-inflammatory microneedle patch for accelerating biofilm-infected diabetic wound healing via modulating the insulin pathway

Macrophages play a pivotal role in the healing of diabetic ulcers. The sustained elevation of glucose levels damages the insulin signaling pathway in macrophages, leading to dysfunctional macrophages that struggle to transition from pro-inflammatory (M1) to reparative (M2) states. Therefore, modulating macrophage inflammatory responses via the insulin pathway holds promise for diabetic ulcer treatment. Additionally, the presence of biofilm impedes drug penetration, and the resulting immunosuppressive microenvironment exacerbates the persistent infiltration of pro-inflammatory M1 macrophages. Therefore, we designed an array of dissolvable microneedle (denoted as NPF@MN) loaded with self-assembled nanoparticles that could deliver NPF nanoparticles, acid-sensitive NPF-releasing Protocatechualdehyde (PA) with hypoglycemic and insulin-like effects, regulating macrophage polarization to an anti-inflammatory M2 phenotype. Additionally, this study extensively examined the mechanism by which NPF@MN accelerates the healing of diabetic ulcers through the activation of the insulin signaling pathway. Through RNA-seq and GSEA analysis, we identified a reduction in the expression of pathway-related factors such as IR, IRS-1, IRS-2, and SHC. Our work presents an innovative therapeutic approach targeting the insulin pathway in diabetic ulcers and underscores its translational potential for clinical management.

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

BackgroundChronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide, characterized by persistent respiratory symptoms and airflow limitation. The involvement of C–C motif chemokine ligand 2 (CCL2) in COPD pathogenesis, particularly in macrophage regulation and activation, is poorly understood despite its recognized role in chronic inflammation. Our study aims to elucidate the regulatory role and molecular mechanisms of CCL2 in the pathogenesis of COPD, providing new insights for therapeutic strategies.MethodsThis study focused on the CCL2-CCR2 signaling pathway, exploring its role in COPD pathogenesis using both Ccl2 knockout (KO) mice and pharmacological inhibitors. To dissect the underlying mechanisms, we employed various in vitro and in vivo methods to analyze the secretion patterns and pathogenic effects of CCL2 and its downstream molecular signaling through the CCL2-CCR2 axis.ResultsElevated Ccl2 expression was confirmed in the lungs of COPD mice and was associated with enhanced recruitment and activation of macrophages. Deletion of Ccl2 in knockout mice, as well as treatment with a Ccr2 inhibitor, resulted in protection against CS- and LPS-induced alveolar injury and airway remodeling. Mechanistically, CCL2 was predominantly secreted by bronchial epithelial cells in a process dependent on STAT1 phosphorylation and acted through the CCR2 receptor on macrophages. This interaction activated the PI3K-AKT signaling pathway, which was pivotal for macrophage activation and the secretion of inflammatory cytokines, further influencing the progression of COPD.ConclusionsThe study highlighted the crucial role of CCL2 in mediating inflammatory responses and remodeling in COPD. It enhanced our understanding of COPD's molecular mechanisms, particularly how CCL2's interaction with the CCR2 activates critical signaling pathways. Targeting the CCL2-CCR2 axis emerged as a promising strategy to alleviate COPD pathology.Graphical

Macrophage and Neutrophil Dysfunction in Diabetic Wounds.

Significance: The incidence of diabetes continues to rise throughout the world in an alarming rate. Diabetic patients often develop diabetic foot ulcers (DFUs), many of which do not heal. Non-healing DFUs are a major cause of hospitalization, amputation, and increased morbidity. Understanding the underlying mechanisms of impaired healing in DFU is crucial for its management. Recent Advances: This review focuses on the recent advancements on macrophages and neutrophils in diabetic wounds and DFUs. In particular, we discuss diabetes-induced dysregulations and dysfunctions of macrophages and neutrophils. Critical Issues: It is well established that diabetic wounds are characterized by stalled inflammation that results in impaired healing. Recent findings in the field suggest that dysregulation of macrophages and neutrophils plays a critical role in impaired healing in DFUs. The delineation of mechanisms that restore macrophage and neutrophil function in diabetic wound healing is the focus of intense investigation. Future Directions: The breadth of recently generated knowledge on the activity of macrophages and neutrophils in diabetic wound healing is impressive. Experimental models have delineated pathways that hold promise for the treatment of diabetic wounds and DFUs. These pathways may be useful targets for further clinical investigation.

Atherosclerosis associated with Chlamydia pneumoniae: Dissecting the etiology

Chlamydia pneumoniae related infections and atherosclerosis are both common entities. Today, the literature presents an enormous amount of data regarding the role of C. pneumoniae in the development and sustainment of atherosclerosis and allowing us to comprehend the molecular mechanisms behind better. The implications of C. pneumoniae in atherogenesis include altered platelet function, hypercoagulability, macrophage dysfunction, vascular smooth muscle proliferation, and increased neutrophilic migration. Therefore, it would not be wrong to implicate that, C. pneumoniae plays important roles in almost every stage of atherogenesis. Furthermore, various serological markers suggestive of active or past C. pneumoniae infection are known to be associated with multiple clinical presentations, such as abdominal aortic aneurysms, subclinical atherosclerosis in the young individuals, aggravated atherosclerosis in heterozygous familial hypercholesterolemia. This review, as a result, aims to provide detailed insights into the pathophysiological mechanisms of atherogenesis associated with C. pneumoniae and its clinical implications.