Clearance Of Debris Research Articles

Synthetic cannabinoids reduce the inflammatory activity of microglia and subsequently improve neuronal survival in vitro

Microglia are resident immune cells of the brain that survey the microenvironment, provide trophic support to neurons, and clear debris to maintain homeostasis and healthy brain function. Microglia are also drivers of neuroinflammation in several neurodegenerative diseases. Microglia produce endocannabinoids and express both cannabinoid receptor subtypes suggesting that this system is a target to suppress neuroinflammation. We tested whether cannabinoid type 1 (CB1) or type 2 (CB2) receptors could be targeted selectively or in combination to dampen the pro-inflammatory behavior of microglia, and whether this would have functional relevance to decrease secondary neuronal damage. We determined that components of the endocannabinoid system were altered when microglia are treated with lipopolysaccharide and interferon-gamma and shift to a pro-inflammatory phenotype. Furthermore, pro-inflammatory microglia released cytotoxic factors that induced cell death in cultured STHdhQ7/Q7 neurons. Treatment with synthetic cannabinoids that were selective for CB1 receptors (ACEA) or CB2 receptors (HU-308) dampened the release of nitric oxide (NO) and pro-inflammatory cytokines and decreased levels of mRNA for several pro-inflammatory markers. A nonselective agonist (CP 55,940) exhibited similar influence over NO release but to a lesser extent relative to ACEA or HU-308. All three classes of synthetic cannabinoids ultimately reduced the secondary damage to the cultured neurons. The mechanism for the observed neuroprotective effects appeared to be related to cannabinoid-mediated suppression of MAPK signaling in microglia. Taken together, the data indicate that activation of CB1 or CB2 receptors interfered with the pro-inflammatory activity of microglia in a manner that also reduced secondary damage to neurons.

The Good and the Bad: Monocytes' and Macrophages' Diverse Functions in Inflammation.

Monocytes and macrophages are central players of the innate immune response and play a pivotal role in the regulation of inflammation. Thereby, they actively participate in all phases of the immune response, from initiating inflammation and triggering the adaptive immune response, through to the clearance of cell debris and resolution of inflammation. In this review, we described the mechanisms of monocyte and macrophage adaptation to rapidly changing microenvironmental conditions and discussed different forms of macrophage polarization depending on the environmental cues or pathophysiological condition. Therefore, special focus was placed on the tight regulation of the pro- and anti-inflammatory immune response, and the diverse functions of S100A8/S100A9 proteins and the scavenger receptor CD163 were highlighted, respectively. We paid special attention to the function of pro- and anti-inflammatory macrophages under pathological conditions.

Abstract 1329: Maresins prevent breast cancer dormancy escape via resolution of inflammation

Abstract Cytotoxic cancer therapies reduce tumor burden by killing tumor cells. However, the resulting apoptotic and necrotic cell bodies (tumor cell “debris”) may stimulate tumor initiation and progression by disrupting the resolution of inflammation. Thus, chemotherapy and anti-estrogen breast cancer therapy, including tamoxifen, may be a double-edged sword. A paradigm shift is emerging in understanding the resolution of inflammation as an active biochemical process with the discovery of novel specialized pro-resolving lipid autocoid mediators (SPMs), such as maresins and endogenous resolution programs. Despite approaches to block systemic inflammation, there are no current “pro-resolving” therapies in cancer. To determine whether debris stimulates breast cancer growth, we utilized tumor dormancy models with a subthreshold (nontumorigenic) inoculum of tumor cells. We demonstrated that breast tumor “debris” generated by cytotoxic anti-estrogen therapy (tamoxifen or fulvestrant) or chemotherapy (eribulin) stimulates dormancy escape by triggering a macrophage-derived pro-inflammatory and pro-angiogenic “cytokine storm”. Thus, tumor cell debris is a critical pro-tumorigenic factor in breast cancer initiation and progression. To assess whether stimulating the clearance of debris would suppress breast cancer progression, we utilized the SPMs maresin 1 (MaR1) and maresin conjugates in tissue regeneration (MCTR1, MCTR2). Each maresin (MaR1, MCTR1 and MCTR2) sharply reduced tumor growth in both debris-stimulated and spontaneous (e.g. MMTV-PyMT) breast cancer models at nanogram concentrations (15 ng/day) without toxicity. Notably, maresins enhanced immunotherapy (anti-CTLA4) to induce tumor regression in estrogen receptor (ER) positive (EO771) and inhibit ER negative tumor growth (4T1). Maresins stimulated macrophage phagocytosis of therapy (fulvestrant and tamoxifen)-generated breast cancer debris at only nanomolar concentrations (0.1 - 10 nM). Remarkably, maresins alone or in combination with chemotherapy (paclitaxel) reduced levels of pro-angiogenic factors (e.g. CXCL12/SDF-1) in the tumor microenvironment and decreased microvessel density/size, thereby inhibiting tumor angiogenesis. Maresins dampened the therapy-induced cytokine storm, by reducing levels of TNF-α, MIP-2/CXCL2, CCL2/MCP-1, IL-1ra/IL-1F3, CCL5, CXCL13, Serpin E1/PAI-1, IL-1β and G-CSF both in vitro in debris-stimulated macrophages and in vivo in plasma and tumor tissue. Stimulating the resolution of inflammation via pro-resolution lipid mediators to enhance immunotherapy is a novel host-centric therapeutic approach to prevent breast cancer initiation, dormancy escape and tumor progression via debris clearance and counter-regulation of the cytokine storm. Altogether, the maresin pathway mediators may represent a new therapeutic approach to stimulate the resolution of inflammation in breast cancer. Citation Format: Franciele Cristina Kipper, Jianjun Deng, Eva Rothenberger, Abigail Kelly, Madeline Duncan, Sui Huang, Charles N. Serhan, Dipak Panigrahy. Maresins prevent breast cancer dormancy escape via resolution of inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1329.

Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis.

HIV-neurocognitive impairment (HIV-NCI) can be a debilitating condition for people with HIV (PWH), despite the success of antiretroviral therapy (ART). Substance use disorder is often a comorbidity with HIV infection. The use of methamphetamine (meth) increases systemic inflammation and CNS damage in PWH. Meth may also increase neuropathogenesis through the functional dysregulation of cells that harbor HIV. Perivascular macrophages are long-lived reservoirs for HIV in the CNS. The impaired clearance of extracellular debris and increased release of reactive oxygen species (ROS) by HIV-infected macrophages cause neurotoxicity. Macroautophagy is a vital intracellular pathway that can regulate, in part, these deleterious processes. We found in HIV-infected primary human macrophages that meth inhibits phagocytosis of aggregated amyloid-β, increases total ROS, and dysregulates autophagic processes. Treatment with widely prescribed ART drugs had minimal effects, although there may be an improvement in phagocytosis when co-administered with meth. Pharmacologically inhibited lysosomal degradation, but not induction of autophagy, further increased ROS in response to meth. Using mass spectrometry, we identified the differentially expressed proteins in meth-treated, HIV-infected macrophages that participate in phagocytosis, mitochondrial function, redox metabolism, and autophagy. Significantly altered proteins may be novel targets for interventional strategies that restore functional homeostasis in HIV-infected macrophages to improve neurocognition in people with HIV-NCI using meth.

Transforming growth factor-beta signaling modulates perineurial glial bridging following peripheral spinal motor nerve injury in zebrafish.

Spinal motor nerves are necessary for organismal locomotion and survival. In zebrafish and most vertebrates, these peripheral nervous system structures are composed of bundles of axons that naturally regenerate following injury. However, the cellular and molecular mechanisms that mediate this process are still only partially understood. Perineurial glia, which form a component of the blood‐nerve barrier, are necessary for the earliest regenerative steps by establishing a glial bridge across the injury site as well as phagocytosing debris. Without perineurial glial bridging, regeneration is impaired. In addition to perineurial glia, Schwann cells, the cells that ensheath and myelinate axons within the nerve, are essential for debris clearance and axon guidance. In the absence of Schwann cells, perineurial glia exhibit perturbed bridging, demonstrating that these two cell types communicate during the injury response. While the presence and importance of perineurial glial bridging is known, the molecular mechanisms that underlie this process remain a mystery. Understanding the cellular and molecular interactions that drive perineurial glial bridging is crucial to unlocking the mechanisms underlying successful motor nerve regeneration. Using laser axotomy and in vivo imaging in zebrafish, we show that transforming growth factor‐beta (TGFβ) signaling modulates perineurial glial bridging. Further, we identify connective tissue growth factor‐a (ctgfa) as a downstream effector of TGF‐β signaling that works in a positive feedback loop to mediate perineurial glial bridging. Together, these studies present a new signaling pathway involved in the perineurial glial injury response and further characterize the dynamics of the perineurial glial bridge.

Engineered Schwann Cell-Based Therapies for Injury Peripheral Nerve Reconstruction.

Compared with the central nervous system, the adult peripheral nervous system possesses a remarkable regenerative capacity, which is due to the strong plasticity of Schwann cells (SCs) in peripheral nerves. After peripheral nervous injury, SCs de-differentiate and transform into repair phenotypes, and play a critical role in axonal regeneration, myelin formation, and clearance of axonal and myelin debris. In view of the limited self-repair capability of SCs for long segment defects of peripheral nerve defects, it is of great clinical value to supplement SCs in necrotic areas through gene modification or stem cell transplantation or to construct tissue-engineered nerve combined with bioactive scaffolds to repair such tissue defects. Based on the developmental lineage of SCs and the gene regulation network after peripheral nerve injury (PNI), this review summarizes the possibility of using SCs constructed by the latest gene modification technology to repair PNI. The therapeutic effects of tissue-engineered nerve constructed by materials combined with Schwann cells resembles autologous transplantation, which is the gold standard for PNI repair. Therefore, this review generalizes the research progress of biomaterials combined with Schwann cells for PNI repair. Based on the difficulty of donor sources, this review also discusses the potential of “unlimited” provision of pluripotent stem cells capable of directing differentiation or transforming existing somatic cells into induced SCs. The summary of these concepts and therapeutic strategies makes it possible for SCs to be used more effectively in the repair of PNI.

D-4F, an apolipoprotein A-I mimetic, promotes the clearance of myelin debris and the reduction of foamy macrophages after spinal cord injury

ABSTRACT After spinal cord injury (SCI), a large number of blood-derived macrophages infiltrate the lesion site and phagocytose myelin debris to become foamy macrophages, which leads to chronic inflammation. The drug D-4F, an apolipoprotein A-I peptidomimetic made of D-amino acids, has been reported to promote the lipid metabolism of foamy macrophages in atherosclerosis. However, the role and mechanism of D-4F in SCI are still unclear. In this study, we found that D-4F can promote the removal of myelin debris, reduce the formation of foamy macrophages in the lesion core and promote neuroprotection and recovery of motor function after SCI. These beneficial functions of D-4F may be related to its ability to upregulate the expression of ATP-binding cassette transporter A1 (ABCA1), the main transporter that mediates lipid efflux in foamy macrophages because inhibiting the activity of ABCA1 can reverse the effect of D-4F in vitro. In conclusion, D-4F may be a promising candidate for treating SCI by promoting the clearance of myelin debris by foamy macrophages via the ABCA1 pathway.

Protectins Inhibit Estrogen Receptor Negative Breast Cancer Growth in Mice

Cytotoxic breast cancer therapies reduce tumor burden by killing tumor cells, yet simultaneously generates tumor cell debris. Apoptotic and necrotic debris that are not cleared by the immune system create a pro‐inflammatory microenvironment, fueling tumor burden by disrupting the resolution of inflammation. A paradigm shift is emerging in understanding the resolution of inflammation as an active biochemical process with the discovery of novel specialized pro‐resolving lipid autocoid mediators (SPMs), such as resolvins (Rvs) and protectin conjugates in tissue regeneration (PCTRs), as well as endogenous resolution programs. We have previously reported in mice models that resolvins (e.g. RvD1, RvD2, and RvE1) reduce tumor growth, however the role of protectins in cancer remains unknown. To assess whether stimulating the resolution of inflammation would inhibit breast cancer progression, we utilized protectin (PCTR1) to treat established models of estrogen receptor (ER) positive (EO771) and negative breast cancer (4T1). PCTR1 sharply reduced tumor growth in the EO771 and 4T1 breast cancer models at only nanogram concentrations (15 ng/day) without toxicity when administered alone or in combination with chemotherapy (paclitaxel) and/or immunotherapy (anti‐cytotoxic T‐lymphocyte‐associated protein 4, CTLA4). Notably, PCTR1 inhibited tumor growth in combination with immunotherapy (anti‐CTLA4) or immunotherapy plus chemotherapy (paclitaxel) in ER positive (EO771) breast cancer. Also, PCTR1 inhibited ER negative tumor growth (4T1) alone and in combination with paclitaxel and/or anti‐CTLA4. Remarkably, PCTR1 alone or in combination with chemotherapy (paclitaxel) reduced gene expression and protein levels of pro‐angiogenic factor CXCL12/SDF‐1 in the tumor microenvironment. PCTR1 dampened the therapy‐induced cytokine storm, by counter‐regulating levels of TNF‐α, CCL2/MCP‐1, CXCL10, CCL5, CXCL13, and IL‐1β in vivo. Taken together, we demonstrate that PCTR1, a pro‐resolution lipid mediator, inhibits breast cancer progression via debris clearance and counter‐regulation of the cytokine storm. The use of protectins to enhance immunotherapy is a novel approach to inhibit breast cancer progression via resolution of inflammation that remains to be evaluated in humans.

Myeloid Expressed Epidermal Growth Factor Receptor (EGFR) is Critical to Heart Homeostasis and Limits Adverse Outcomes Following Ischemic Attack

The healthy heart comprises immune cells, mainly macrophages of differing class and origin. While these myeloid cells remain an area of continuous investigation, we have come to appreciate that a subset of tissue residing macrophages (TRMs) seed the heart during development and are maintained through self‐renewal. Further, TRMs continue to be linked to the maintenance of cardiac homeostasis, for instance, through facilitating crosstalk with other cardiac cells, and participating in immunosurveillance. In the case of injury however, such as a myocardial infarction (MI), TRMs are largely replaced by circulating and recruited myeloid cells. Post‐infarct macrophages (mf) are greater in number and class, and functionally, debris clearance and initiation of cardiac repair mechanisms becomes their utmost priority to limit the severity of heart failure (HF). Given these significant roles, it has become critical to understand how cardiac myeloid cells are regulated, and what mechanisms contribute to their known functions both at steady‐state and following injury. Epidermal growth factor receptor (EGFR) is a cell surface tyrosine kinase receptor known to govern cell function through myriad processes. Although historically studied as an oncogene, EGFR has been shown to regulate cardiac physiology, and notably mf activation, survival and function. However, it is currently unknown whether EGFR influences myeloid homeostasis within the heart. Thus, we have generated myeloid‐specific EGFR knockout mice (EGFRmylKO) by crossing floxed EGFR (EGFRf/f) with LysM Cre mice and performed comparative analyses between the lines at baseline and following injury. In response to MI, EGFRmylKO mice exhibit altered inflammatory responses, resulting in aggravated cardiac dysfunction, exacerbated hypertrophic remodeling, and limited angiogenic repair. These functional and structural outcomes are preceded by a disruption in the post‐injury myeloid cell infiltration continuum that favors adequate repair, resulting in decreased transcripts of reparative factors including IL‐10. Additionally, EGFRmylKO mouse hearts show modest signs of stress at baseline, in the absence of injury, including cardiomyocyte hypertrophy with an associated increase in expression of signature fetal gene transcripts. Whole transcriptome analysis of cardiac resident myeloid (Cd11b+) cells by RNASeq revealed over 700 differentially expressed genes that were significantly altered between EGFRmylKO and EGFRf/f control mice. Among these are IGFBP family members 5 and 7, each known to regulate IGF availability, which itself has been recently shown to influence cardiac hypertrophy. In sum, our results reveal that myeloid cell‐expressed EGFR plays previously unknown roles in the regulation of the cardiac homeostasis baseline as well as the chronic remodeling response to ischemic injury.

Erythropoietin M2 macrophage Signaling Promotes Schwann Cells Clearance and Functional Recovery Following Peripheral Nerve Injury

BackgroundTraumatic peripheral nerve injury (TPNI) obliterates axons and Schwann cells (SCs) that must be cleared through phagocytosis to allow surviving SCs to de‐differentiate and divide and guide the regeneration process. In TPNI, macrophage (MØ) infiltration and early phenotypic transitions (M1 to M2) are critical for the phagocytosis of SCs debris. Delayed phagocytosis critically aggravates inflammation and impairs MØ function, which leads to failure to advance SC orchestration and neuronal regeneration. Erythropoietin (EPO), a pluripotent hormone, helps to guide MØs and SC transition post‐TPNI. The significance of the effects of EPO on debris clearance, apoptosis, myelination, and functional improvement is unknown, despite much effort motivating clinical translation of EPO for TPNI. We hypothesized that a role in supporting M2 phenotype macrophages after TPNI might explain EPO’s neuroprotective function through SCs debris clearance.Methods and ResultsWe evaluated EPO’s effect on sciatic nerve crush injury (SNCI) and found EPO treatment (5000 IU/kg, intraperitoneally, post‐surgery days 1, 2, and 3,) increased myelination and sciatic functional index (SFI) and augmented anti‐apoptosis and phagocytosis of myelin debris via CD206+ macrophages when compared to saline treatment in the mouse. EPO increased efferocytosis of apoptotic sciatic nerve derived Schwann cells (SNSCs) both in bone marrow derived macrophages (BMMØs) and peritoneal derived macrophages (PMØs) in‐vitro, as well as in PMØs in‐vivo by immunofluorescence (IF) and flow cytometry. EPO treatment significantly attenuated BMMØ pro‐inflammatory genes (IL1b, iNOS, and CD68) and augmented anti‐inflammatory genes (IL10, and CD163) in addition to the cell surface marker CD206 expression after lipopolysaccharide (LPS) induction. EPO also showed anti‐apoptotic (Annexin V/ 7AAD) effects in BMMØs. Our data demonstrate that EPO promotes the M2 phenotype macrophages to ameliorate SN apoptosis and efferocytosis of dying SCs and myelin debris and improves SN functional recovery following SNCI.ConclusionsTo the best of our knowledge, this is the first study to demonstrate EPO’s ameliorative effect on the progression of post‐TPNI via M2 phenotype macrophage phagocytosis of SCs debris with early anti‐apoptotic and anti‐inflammatory effects. These data may support the findings of other researchers and might shed light on the role of EPO in improving functional recovery in the traumatized limb.

PD19-09 SEEING IS BELIEVING: OPTIMIZING RENAL PELVIC PRESSURE IMPROVES VISUALIZATION DURING ENDOSCOPIC COMBINED INTRARENAL SURGERY

You have accessJournal of UrologyCME1 May 2022PD19-09 SEEING IS BELIEVING: OPTIMIZING RENAL PELVIC PRESSURE IMPROVES VISUALIZATION DURING ENDOSCOPIC COMBINED INTRARENAL SURGERY Cayde Ritchie, John Hartman, Akin Amasyali, John Jung, Aviram Assidon, Joshua Belle, and D. Duane Baldwin Cayde RitchieCayde Ritchie More articles by this author , John HartmanJohn Hartman More articles by this author , Akin AmasyaliAkin Amasyali More articles by this author , John JungJohn Jung More articles by this author , Aviram AssidonAviram Assidon More articles by this author , Joshua BelleJoshua Belle More articles by this author , and D. Duane BaldwinD. Duane Baldwin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002557.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Endoscopic combined intrarenal surgery (ECIRS), involving percutaneous renal access and retrograde ureteroscopy, achieves high stone free rates by allowing ureteroscopic visualization of calyces difficult to see with an antegrade approach. Visibility during ureteroscopy relies on irrigation through a 3Fr working channel, limiting the ability to clear blood and debris. Low irrigation rates also result in collapse of the collecting system, further limiting calyceal visualization. We have noted that visibility can be improved by placing the irrigation stopcock into the percutaneous sheath. The purpose of this study was to compare renal pelvic pressure (RPP) and retrograde ureteroscopic visibility during ECIRS, with and without access sheath irrigation (ASI), to determine the safety and efficacy of this technique. METHODS: Prospectively collected RPP measurements from 15 patients undergoing ECIRS at a single academic institution were retrospectively reviewed. During retrograde ureteroscopic renal mapping, a pressure monitor was connected to the working channel of a flexible ureteroscope. With the tip of the ureteroscope in the renal pelvis, RPP measurements were performed with and without ASI. Irrigation was maintained at a standard height of 1.28m. Study endpoints were RPP and endoscopic visibility, based on a blinded review of intraoperative photos by ten urologists using a 10-point Likert scale. Statistical analysis was performed using a paired samples t-test and Mann-Whitney U test, with significance defined as p<0.05. RESULTS: Antegrade ASI yielded significantly greater RPP (25.9 vs. 8.5 mmHg, p<0.001) and improved subjective visibility (6.9 vs. 1.9, p<0.001), when compared to ECIRS without antegrade flow. Using ASI, RPP never exceeded the approximate 35 mmHg threshold for pyelovenous backflow. Intra-operative pictures display greater collecting system distension, higher clarity of instruments, and less bleeding obscuring the field (Fig. 1). CONCLUSIONS: Antegrade access sheath irrigation represents a novel strategy for optimizing renal pelvic pressure and endoscopic visibility during ECIRS. Delivering continuous antegrade irrigation is a safe and effective method to improve visibility, without exceeding the threshold for pyelovenous backflow. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e352 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cayde Ritchie More articles by this author John Hartman More articles by this author Akin Amasyali More articles by this author John Jung More articles by this author Aviram Assidon More articles by this author Joshua Belle More articles by this author D. Duane Baldwin More articles by this author Expand All Advertisement PDF DownloadLoading ...

Serum autoantibodyome reveals that healthy individuals share common autoantibodies

SUMMARYAutoantibodies are a hallmark of both autoimmune disease and cancer, but they also occur in healthy individuals. Here, we perform a meta-analysis of nine datasets and focus on the common autoantibodies shared by healthy individuals. We report 77 common autoantibodies based on the protein microarray data obtained from probing 182 healthy individual sera on 7,653 human proteins and an additional 90 healthy individual sera on 1,666 human proteins. There is no gender bias; however, the number of autoantibodies increase with age, plateauing around adolescence. We use a bioinformatics pipeline to determine possible molecular-mimicry peptides that can contribute to the elicitation of these common autoantibodies. There is enrichment of intrinsic properties of proteins like hydrophilicity, basicity, aromaticity, and flexibility for common autoantigens. Subcellular localization and tissue-expression analysis reveal that several common autoantigens are sequestered from the circulating autoantibodies.

P548. Glymphatic System in Schizophrenia: An H-MRS High-Molecular-Weight Macromolecules Study

Waste clearance in the brain is mediated through the glymphatic system, which has been explored in neurodegeneration, sleep, and aging. Genetic, metabolic-vascular, and neuroimaging evidence suggest that clearance of debris via the glymphatic system is affected in schizophrenia (SCZ). We aimed to quantify the aggregation of high-molecular-weight macromolecules (MM), as a measure of compromised glymphatic system, in patients with SCZ. We hypothesised: 1) patients with SCZ would have higher MM levels than controls; 2) Age would be associated with less glymphatic system efficiency in both SCZ and controls.

Lesion-associated microglia and macrophages mediate corralling and react with massive phagocytosis for debris clearance and wound healing after LPS-induced dopaminergic depletion

Neuroinflammation contributes to neuronal degeneration in Parkinson's disease (PD). However, how brain inflammatory factors mediate the progression of neurodegeneration is still poorly understood. Experimental models of PD have shed light on the understanding of this phenomenon, but the exploration of inflammation-driven models is necessary to better characterize this aspect of the disorder. The use of lipopolysaccharide (LPS) to induce a neuroinflammation-mediated neuronal loss is useful to induce reliable elimination of dopaminergic neurons. Nevertheless, how this model parallels the PD-like neuroinflammation is uncertain. In the present work, we used the direct LPS injection as a model inductor to eliminate dopaminergic neurons of the substantia nigra pars compacta (SNpc) in rats and reevaluated the inflammatory reaction. High-resolution 3D histological examination revealed that, although LPS induced a reliable elimination of SNpc dopaminergic neurons, it also generated a massive inflammatory response. This inflammation-mediated injury was characterized by corralling, a damaged parenchyma occupied by a vast population of lesion-associated microglia and macrophages (LAMMs) undertaking wound compaction and scar formation, surrounded by highly reactive astrocytes. LAMMs tiled the entire lesion and engaged in long-standing phagocytic activity to resolve the injury. Additionally, modeling LPS inflammation in a cell culture system helped to understand the role of phagocytosis and cytotoxicity in the initial phases of dopaminergic degeneration and indicated that LAMM-mediated toxicity and phagocytosis coexist during LPS-mediated dopaminergic elimination. However, this type of severe inflammatory-mediated injury, and subsequent resolution appear to be different from the ageing-related PD scenario where the architectural structure of the parenchyma is mostly preserved. Thus, the necessity to explore new experimental models to properly mimic the inflammatory compound observed in PD degeneration.

Properties and Functions of Fibroblasts and Myofibroblasts in Myocardial Infarction

The adult mammalian heart contains abundant interstitial and perivascular fibroblasts that expand following injury and play a reparative role but also contribute to maladaptive fibrotic remodeling. Following myocardial infarction, cardiac fibroblasts undergo dynamic phenotypic transitions, contributing to the regulation of inflammatory, reparative, and angiogenic responses. This review manuscript discusses the mechanisms of regulation, roles and fate of fibroblasts in the infarcted heart. During the inflammatory phase of infarct healing, the release of alarmins by necrotic cells promotes a pro-inflammatory and matrix-degrading fibroblast phenotype that may contribute to leukocyte recruitment. The clearance of dead cells and matrix debris from the infarct stimulates anti-inflammatory pathways and activates transforming growth factor (TGF)-β cascades, resulting in the conversion of fibroblasts to α-smooth muscle actin (α-SMA)-expressing myofibroblasts. Activated myofibroblasts secrete large amounts of matrix proteins and form a collagen-based scar that protects the infarcted ventricle from catastrophic complications, such as cardiac rupture. Moreover, infarct fibroblasts may also contribute to cardiac repair by stimulating angiogenesis. During scar maturation, fibroblasts disassemble α-SMA+ stress fibers and convert to specialized cells that may serve in scar maintenance. The prolonged activation of fibroblasts and myofibroblasts in the infarct border zone and in the remote remodeling myocardium may contribute to adverse remodeling and to the pathogenesis of heart failure. In addition to their phenotypic plasticity, fibroblasts exhibit remarkable heterogeneity. Subsets with distinct phenotypic profiles may be responsible for the wide range of functions of fibroblast populations in infarcted and remodeling hearts.

Inflammation and resolution signaling in cardiac repair and heart failure.

SummaryUnresolved inflammation is a key mediator of advanced heart failure. Especially, damage, pathogen, and lifestyle-associated molecular patterns are the major factors in initiating baseline inflammatory diseases, particularly in cardiac pathology. After a significant cardiac injury like a heart attack, splenic and circulating leukocytes begin a highly optimized sequence of immune cell recruitment (neutrophils and monocytes) to coordinate effective tissue repair. An injured cardiac tissue repair and homeostasis are dependent on clearance of cellular debris where the recruited leukocytes transition from a pro-inflammatory to a reparative program through resolution process. After a cardiac injury, macrophages play a decisive role in cardiac repair through the biosynthesis of endogenous lipid mediators that ensure a timely tissue repair while avoiding chronic inflammation and impaired cardiac repair. However, dysregulation of resolution of inflammation processes due to cardiometabolic defects (obesity, hypertension, and diabetes), aging, or co-medication(s) lead to impaired cardiac repair. Hence, the presented review demonstrates the fundamental role of leukocytes, in particular macrophages orchestrate the inflammation and resolution biology, focusing on the biosynthesis of specialized lipid mediators in cardiac repair and heart failure. This work was supported by research funds from National Institutes of Health (AT006704, HL132989, and HL144788) to G.V.H. The authors acknowledges the use of Servier Medical Art image bank and Biorender that is used to create schematic Figures 1–3.

Neuron-glia crosstalk in neuronal remodeling and degeneration: Neuronal signals inducing glial cell phagocytic transformation in Drosophila.

Neuronal remodeling is a conserved mechanism that eliminates unwanted neurites and can include the loss of cell bodies. In these processes, a key role for glial cells in events from synaptic pruning to neuron elimination has been clearly identified in the last decades. Signals sent from dying neurons or neurites to be removed are received by appropriate glial cells. After receiving these signals, glial cells infiltrate degenerating sites and then, engulf and clear neuronal debris through phagocytic mechanisms. There are few identified or proposed signals and receptors involved in neuron-glia crosstalk, which induces the transformation of glial cells to phagocytes during neuronal remodeling in Drosophila. Many of these signaling pathways are conserved in mammals. Here, we particularly emphasize the role of Orion, a recently identified neuronal CX3 C chemokine-like secreted protein, which induces astrocyte infiltration and engulfment during mushroom body neuronal remodeling. Although, chemokine signaling was not described previously in insects we propose that chemokine-like involvement in neuron/glial cell interaction is an evolutionarily ancient mechanism.

TFAM-Dependent Mitochondrial Metabolism Is Required for Alveolar Macrophage Maintenance and Homeostasis.

Alveolar macrophages (AMs) are major lung tissue-resident macrophages capable of proliferating and self-renewal in situ. AMs are vital in pulmonary antimicrobial immunity and surfactant clearance. The mechanisms regulating AM compartment formation and maintenance remain to be fully elucidated currently. In this study, we have explored the roles of mitochondrial transcription factor A (TFAM)-mediated mitochondrial fitness and metabolism in regulating AM formation and function. We found that TFAM deficiency in mice resulted in significantly reduced AM numbers and impaired AM maturation in vivo. TFAM deficiency was not required for the generation of AM precursors nor the differentiation of AM precursors into AMs, but was critical for the maintenance of AM compartment. Mechanistically, TFAM deficiency diminished gene programs associated with AM proliferation and self-renewal and promoted the expression of inflammatory genes in AMs. We further showed that TFAM-mediated AM compartment impairment resulted in defective clearance of cellular debris and surfactant in the lung and increased the host susceptibility to severe influenza virus infection. Finally, we found that influenza virus infection in AMs led to impaired TFAM expression and diminished mitochondrial fitness and metabolism. Thus, our data have established the critical function of TFAM-mediated mitochondrial metabolism in AM maintenance and function.

Neuroinflammation, Microglia and Implications for Retinal Ganglion Cell Survival and Axon Regeneration in Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) refers to a pathological condition caused by a direct or indirect insult to the optic nerves, which often leads to a partial or permanent vision deficit due to the massive loss of retinal ganglion cells (RGCs) and their axonal fibers. Retinal microglia are immune-competent cells residing in the retina. In rodent models of optic nerve crush (ONC) injury, resident retinal microglia gradually become activated, form end-to-end alignments in the vicinity of degenerating RGC axons, and actively internalized them. Some activated microglia adopt an amoeboid morphology that engulf dying RGCs after ONC. In the injured optic nerve, the activated microglia contribute to the myelin debris clearance at the lesion site. However, phagocytic capacity of resident retinal microglia is extremely poor and therefore the clearance of cellular and myelin debris is largely ineffective. The presence of growth-inhibitory myelin debris and glial scar formed by reactive astrocytes inhibit the regeneration of RGC axons, which accounts for the poor visual function recovery in patients with TON. In this Review, we summarize the current understanding of resident retinal microglia in RGC survival and axon regeneration after ONC. Resident retinal microglia play a key role in facilitating Wallerian degeneration and the subsequent axon regeneration after ONC. However, they are also responsible for producing pro-inflammatory cytokines, chemokines, and reactive oxygen species that possess neurotoxic effects on RGCs. Intraocular inflammation triggers a massive influx of blood-borne myeloid cells which produce oncomodulin to promote RGC survival and axon regeneration. However, intraocular inflammation induces chronic neuroinflammation which exacerbates secondary tissue damages and limits visual function recovery after ONC. Activated retinal microglia is required for the proliferation of oligodendrocyte precursor cells (OPCs); however, sustained activation of retinal microglia suppress the differentiation of OPCs into mature oligodendrocytes for remyelination after injury. Collectively, controlled activation of retinal microglia and infiltrating myeloid cells facilitate axon regeneration and nerve repair. Recent advance in single-cell RNA-sequencing and identification of microglia-specific markers could improve our understanding on microglial biology and to facilitate the development of novel therapeutic strategies aiming to switch resident retinal microglia’s phenotype to foster neuroprotection.

In Vivo Clearance of Apoptotic Debris From Tumor Xenografts Exposed to Chemically Modified Tetrac: Is There a Role for Thyroid Hormone Analogues in Efferocytosis?

Apoptosis is induced in cancer cells and tumor xenografts by the thyroid hormone analogue tetraiodothyroacetic acid (tetrac) or chemically modified forms of tetrac. The effect is initiated at a hormone receptor on the extracellular domain of plasma membrane integrin αvβ3. The tumor response to tetrac includes 80% reduction in size of glioblastoma xenograft in two weeks of treatment, with absence of residual apoptotic cancer cell debris; this is consistent with efferocytosis. The molecular basis for efferocytosis linked to tetrac is incompletely understood, but several factors are proposed to play roles. Tetrac-based anticancer agents are pro-apoptotic by multiple intrinsic and extrinsic pathways and differential effects on specific gene expression, e.g., downregulation of the X-linked inhibitor of apoptosis (XIAP) gene and upregulation of pro-apoptotic chemokine gene, CXCL10. Tetrac also enhances transcription of chemokine CXCR4, which is relevant to macrophage function. Tetrac may locally control the conformation of phagocyte plasma membrane integrin αvβ3; this is a cell surface recognition system for apoptotic debris that contains phagocytosis signals. How tetrac may facilitate the catabolism of the engulfed apoptotic cell debris requires additional investigation.