scholarly journals Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation

2020 ◽  
Author(s):  
Ryan G. Snodgrass ◽  
Yvonne Benatzy ◽  
Tobias Schmid ◽  
Dmitry Namgaladze ◽  
Malwina Mainka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tissue Repair ◽  
Cell Function ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Th2 Cytokines ◽  
Alternatively Activated Macrophages ◽  
Anti Inflammatory ◽  
Alternatively Activated

Abstract Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.

scholarly journals Skin Immunomodulation during Regeneration: Emerging New Targets

2021 ◽  
Vol 11 (2) ◽  
pp. 85
Author(s):  
Loubna Mazini ◽  
Luc Rochette ◽  
Yousra Hamdan ◽  
Gabriel Malka
Keyword(s):  
Cell Proliferation ◽  
Tissue Repair ◽  
Inflammatory Responses ◽  
Skin Barrier ◽  
Adipose Derived Stem Cells ◽  
T And B Cells ◽  
Tumor Growth Factor ◽  
Anti Inflammatory ◽  
Skin Function ◽  
Epidermal Regeneration

Adipose-Derived Stem Cells (ADSC) are present within the hypodermis and are also expected to play a pivotal role in wound healing, immunomodulation, and rejuvenation activities. They orchestrate, through their exosome, the mechanisms associated to cell differentiation, proliferation, and cell migration by upregulating genes implicated in different functions including skin barrier, immunomodulation, cell proliferation, and epidermal regeneration. ADSCs directly interact with their microenvironment and specifically the immune cells, including macrophages and T and B cells, resulting in differential inflammatory and anti-inflammatory mechanisms impacting, in return, ADSCs microenvironment and thus skin function. These useful features of ADSCs are involved in tissue repair, where the required cell proliferation, angiogenesis, and anti-inflammatory responses should occur rapidly in damaged sites. Different pathways involved have been reported such as Growth Differentiation Factor-11 (GDF11), Tumor Growth Factor (TGF)-β, Metalloproteinase (MMP), microRNA, and inflammatory cytokines that might serve as specific biomarkers of their immunomodulating capacity. In this review, we try to highlight ADSCs’ network and explore the potential indicators of their immunomodulatory effect in skin regeneration and aging. Assessment of these biomarkers might be useful and should be considered when designing new clinical therapies using ADSCs or their specific exosomes focusing on their immunomodulation activity.

scholarly journals High-Throughput Screening for CEBPD-Modulating Compounds in THP-1-Derived Reporter Macrophages Identifies Anti-Inflammatory HDAC and BET Inhibitors

2021 ◽  
Vol 22 (6) ◽  
pp. 3022
Author(s):  
Tatjana Ullmann ◽  
Sonja Luckhardt ◽  
Markus Wolf ◽  
Michael J. Parnham ◽  
Eduard Resch
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
High Throughput ◽  
Transcription Initiation ◽  
High Throughput Screening ◽  
Inflammatory Responses ◽  
Hdac Inhibitors ◽  
Screening Assay ◽  
Bet Inhibitors ◽  
Anti Inflammatory

This study aimed to identify alternative anti-inflammatory compounds that modulate the activity of a relevant transcription factor, CCAAT/enhancer binding protein delta (C/EBPδ). C/EBPδ is a master regulator of inflammatory responses in macrophages (Mϕ) and is mainly regulated at the level of CEBPD gene transcription initiation. To screen for CEBPD-modulating compounds, we generated a THP-1-derived reporter cell line stably expressing secreted alkaline phosphatase (SEAP) under control of the defined CEBPD promoter (CEBPD::SEAP). A high-throughput screening of LOPAC®1280 and ENZO®774 libraries on LPS- and IFN-γ-activated THP-1 reporter Mϕ identified four epigenetically active hits: two bromodomain and extraterminal domain (BET) inhibitors, I-BET151 and Ro 11-1464, as well as two histone deacetylase (HDAC) inhibitors, SAHA and TSA. All four hits markedly and reproducibly upregulated SEAP secretion and CEBPD::SEAP mRNA expression, confirming screening assay reliability. Whereas BET inhibitors also upregulated the mRNA expression of the endogenous CEBPD, HDAC inhibitors completely abolished it. All hits displayed anti-inflammatory activity through the suppression of IL-6 and CCL2 gene expression. However, I-BET151 and HDAC inhibitors simultaneously upregulated the mRNA expression of pro-inflammatory IL-1ß. The modulation of CEBPD gene expression shown in this study contributes to our understanding of inflammatory responses in Mϕ and may offer an approach to therapy for inflammation-driven disorders.

Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Staley A. Brod
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Cognitive Decline ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Type I ◽  
Type I Ifn ◽  
Anti Inflammatory

Systemic inflammation is an organism’s response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer’s disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the “principal culprit” in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

scholarly journals Squalene Stimulates a Key Innate Immune Cell to Foster Wound Healing and Tissue Repair

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Cristina Sánchez-Quesada ◽  
Alicia López-Biedma ◽  
Estefania Toledo ◽  
José J. Gaforio
Keyword(s):  
Wound Healing ◽  
Inflammatory Cytokines ◽  
Tissue Repair ◽  
Immune Cell ◽  
Critical Role ◽  
Virgin Olive Oil ◽  
Skin Damage ◽  
Macrophage Response ◽  
Anti Inflammatory ◽  
Minor Compounds

Anti-inflammatory effects of virgin olive oil (VOO) have been described recently, along with its wound healing effect. One of the main minor compounds found in VOO is squalene (SQ), which also possesses preventive effects against skin damage and anti-inflammatory properties. The inflammatory response is involved in wound healing and manages the whole process by macrophages, among others, as the main innate cells with a critical role in the promotion and resolution of inflammation for tissue repair. Because of that, this work is claimed to describe the role that squalene exerts in the immunomodulation of M1 proinflammatory macrophages, which are the first cells implicate in recent injuries. Pro- and anti-inflammatory cytokines were analysed using TPH1 cell experimental model. SQ induced an increase in the synthesis of anti-inflammatory cytokines, such as IL-10, IL-13, and IL-4, and a decrease in proinflammatory signals, such as TNF-α and NF-κB in M1 proinflammatory macrophages. Furthermore, SQ enhanced remodelling and repairing signals (TIMP-2) and recruitment signals of eosinophils and neutrophils, responsible for phagocytosis processes. These results suggest that SQ is able to promote wound healing by driving macrophage response in inflammation. Therefore, squalene could be useful at the resolution stage of wound healing.

scholarly journals Deletion of cftr leads to an excessive neutrophilic response and defective tissue repair in a zebrafish model of sterile inflammation

2019 ◽  
Author(s):  
Audrey Bernut ◽  
Catherine A. Loynes ◽  
R. Andres Floto ◽  
Stephen A. Renshaw
Keyword(s):  
Cystic Fibrosis ◽  
Tissue Repair ◽  
Cell Function ◽  
Immune Cell ◽  
Genetic Disorder ◽  
Innate Immune ◽  
Lung Damage ◽  
Tanshinone Iia ◽  
Sterile Inflammation ◽  
Inflammatory Status

AbstractInflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. However, therapeutic targeting of inflammation has been hampered by a lack of understanding of the links between a dysfunctional CFTR and the deleterious innate immune response in CF. Herein, we used CFTR-depleted zebrafish larvae as an innovative in vivo vertebrate model, mimicking aspects of the inflammatory pathology of CF-related lung, to understand how CFTR dysfunction leads to abnormal inflammatory status in CF.We show that impaired CFTR-mediated inflammation correlates with an exuberant neutrophilic response after injury: CF zebrafish exhibit enhanced and sustained accumulation of neutrophils at wounds. Excessive epithelial oxidative responses drive enhanced neutrophil recruitment towards wounds. Persistence of neutrophils at inflamed sites is associated with impaired reverse migration of neutrophils and reduction in neutrophil apoptosis. As a consequence, the increased number of neutrophils at wound sites causes tissue damage and abnormal tissue repair. Importantly, the pro-resolution molecule Tanshinone IIA successfully re-balances inflammation both by accelerating inflammation resolution and by improving tissue repair in CFTR-deficient animal.Larval zebrafish giving a unique insight into innate immune cell function in CFTR deficiency, our findings bring important new understanding of the mechanisms underlying the inflammatory pathology in CF, which could be addressed therapeutically to prevent inflammatory lung damage in CF patients with potential improvements in disease outcomes.

Abstract TP99: Human Lung Endothelial Cell Anti-Inflammatory and Regenerative Responses in Acute Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Nikunj Satani ◽  
Kaavya Giridhar ◽  
Natalia Wewior ◽  
Dominique D Norris ◽  
Scott D Olson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Stroke Severity ◽  
Stroke Patients ◽  
Anti Inflammatory ◽  
Lung Endothelial Cells ◽  
Stroke Mimic

Background: Inflammatory responses after stroke consists of central and peripheral immune responses. The role of the spleen after stroke is well-known, however the role of the lungs has not been studied in detail. We explored the relation between stroke severity and immunomodulatory changes in lung endothelial cells. Methods: Human pulmonary endothelial cells (hPECs, Cell Biologics) were cultured at passage 3. Serum from stroke patients with NIH Stroke Scale (NIHSS) severity ranging from 0 to 20 was collected at 24 hours after stroke. hPECs were exposed to media with 1) 10% FBS alone (N=6), 2) 10% serum from stroke patients (N=72), or 3) 10% serum from stroke mimic patients (N=6). After 3 hour of exposure, fresh media was added and secretomes from hPECs were measured after 24 hours. We isolated RNA from hPECs after 3 hour of serum exposure and measured gene expression (N=6 for each group). Secretome and gene changes in hPECs were analyzed based on stroke severity, tPA treatment, and co-morbidities. Results: Serum from stroke patients reduced the secretion of IL-8, MCP-1 and Fractalkine (p<0.01), and increased the secretion of VEGF and BDNF (p<0.01) from hPECs. These effects were more pronounced depending on stroke severity (Fig). There was no effect of tPA or T2DM on hPECs secretomes. There was significantly reduced gene expression of IL-6, IL-8, MCP-1 and IL-1β and significantly higher expression of ICAM1, IGF-1 and TGF-β1 as compared to stroke mimics. Conclusion: Exposure of hPECs to serum from stroke patients alters their immunomodulatory properties. Higher severity of stroke leads to more protective response from hPECs by reducing the secretion of pro-inflammatory factors, while increasing the secretion of anti-inflammatory factors.

P151 DISRUPTION OF ENDOGENOUS ITACONATE PRODUCTION EXACERBATES EXPERIMENTAL COLITIS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S5-S6
Author(s):  
Ryan Frieler ◽  
Thomas Vigil ◽  
Richard Mortensen ◽  
Yatrik Shah
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Tricarboxylic Acid Cycle ◽  
Myeloid Cells ◽  
Experimental Colitis ◽  
Cell Types ◽  
Cell Phenotype ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Anti Inflammatory

Abstract Background Inflammation is a hallmark of inflammatory bowel disease and alterations in tricarboxylic acid cycle (TCA) metabolism have been identified as major regulators of immune cell phenotype during inflammation and hypoxia. The TCA cycle metabolite, itaconate, is produced by the enzyme aconitate decarboxylase 1 (Acod1) and is highly upregulated during classical macrophage activation and during experimental colitis. Itaconate and cell permeable derivatives have robust anti-inflammatory effects on macrophages, therefore we hypothesized that Acod1-produced itaconate has a protective, anti-inflammatory effect during experimental colitis. Methods and Results Wild type (WT) control and Acod1-/- mice were administered 3% Dextran Sulfate Sodium (DSS) in water for 7 days to induce experimental colitis. After DSS was discontinued, Acod1-/- mice had significantly reduced body weight recovery with increased macroscopic disease severity, and upon dissection had decreased colon length and more severe inflammation. To determine if myeloid cells are the critical Acod1/itaconate-producing cell types, we generated myeloid-specific Acod1 deficient mice, however no differences in weight loss, colon length or inflammatory gene expression were detected compared to WT controls. To test whether supplementation with exogenous itaconate could ameliorate colitis, WT mice were treated with the cell-permeable form of itaconate, dimethyl itaconate (DMI). Administration of DMI significantly improved recovery after 7 days of DSS treatment and significantly reduced inflammatory gene expression in the colon. Conclusion Our data suggest that Acod1-produced itaconate has an important role in the regulation of inflammation during experimental colitis. Although myeloid cells have been thought to be major producers of Acod1 and itaconate, our data indicate that other cell types are involved. These results highlight the importance of this immunometabolic pathway and suggest that preservation or enhancement of this pathway with natural metabolites or metabolite derivatives could have beneficial effects during colitis.

scholarly journals Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5717 ◽  
Author(s):  
Jung-Yeon Kim ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Anti Inflammatory

Sepsis is the major cause of acute kidney injury (AKI) in severely ill patients, but only limited therapeutic options are available. During sepsis, lipopolysaccharide (LPS), an endotoxin derived from bacteria, activates signaling cascades involved in inflammatory responses and tissue injury. Apamin is a component of bee venom and has been shown to exert antioxidative, antiapoptotic, and anti-inflammatory activities. However, the effect of apamin on LPS-induced AKI has not been elucidated. Here, we show that apamin treatment significantly ameliorated renal dysfunction and histological injury, especially tubular injury, in LPS-injected mice. Apamin also suppressed LPS-induced oxidative stress through modulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and heme oxygenase-1. Moreover, tubular cell apoptosis with caspase-3 activation in LPS-injected mice was significantly attenuated by apamin. Apamin also inhibited cytokine production and immune cell accumulation, suppressed toll-like receptor 4 pathway, and downregulated vascular adhesion molecules. Taken together, these results suggest that apamin ameliorates LPS-induced renal injury through inhibiting oxidative stress, apoptosis of tubular epithelial cells, and inflammation. Apamin might be a potential therapeutic option for septic AKI.

scholarly journals A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 280 ◽  
Author(s):  
Berenice Faz-López ◽  
Héctor Mayoral-Reyes ◽  
Rogelio Hernández-Pando ◽  
Pablo Martínez-Labat ◽  
Derek M. McKay ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Tissue Damage ◽  
Tissue Repair ◽  
Inflammatory Responses ◽  
Parasitic Infection ◽  
Toxocara Canis ◽  
Parasitic Infections ◽  
Lung Pathology ◽  
M2 Macrophages ◽  
Alternatively Activated Macrophages

Macrophages that are classically activated (M1) through the IFN-γ/STAT1 signaling pathway have a major role in mediating inflammation during microbial and parasitic infections. In some cases, unregulated inflammation induces tissue damage. In helminth infections, alternatively activated macrophages (M2), whose activation occurs mainly via the IL-4/STAT6 pathway, have a major role in mediating protection against excessive inflammation, and has been associated with both tissue repair and parasite clearance. During the lung migratory stage of Toxocara canis, the roles of M1 and M2 macrophages in tissue repair remain unknown. To assess this, we orally infected wild-type (WT) and STAT1 and STAT6-deficient mice (STAT1−/− and STAT6−/−) with L2 T. canis, and evaluated the role of M1 or M2 macrophages in lung pathology. The absence of STAT1 favored an M2 activation pattern with Arg1, FIZZ1, and Ym1 expression, which resulted in parasite resistance and lung tissue repair. In contrast, the absence of STAT6 induced M1 activation and iNOS expression, which helped control parasitic infection but generated increased inflammation and lung pathology. Next, macrophages were depleted by intratracheally inoculating mice with clodronate-loaded liposomes. We found a significant reduction in alveolar macrophages that was associated with higher lung pathology in both WT and STAT1−/− mice; in contrast, STAT6−/− mice receiving clodronate-liposomes displayed less tissue damage, indicating critical roles of both macrophage phenotypes in lung pathology and tissue repair. Therefore, a proper balance between inflammatory and anti-inflammatory responses during T. canis infection is necessary to limit lung pathology and favor lung healing.

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