Specialized Pro-Resolving Mediators as Potential Regulators of Inflammatory Macrophage Responses in COVID-19

The recent outbreak of SARS-CoV2 has emerged as one of the biggest pandemics of our century, with outrageous health, social and economic consequences globally. Macrophages may lay in the center of COVID-19 pathogenesis and lethality and treatment of the macrophage-induced cytokine storm has emerged as essential. Specialized pro-resolving mediators (SPMs) hold strong therapeutic potentials in the management of COVID-19 as they can regulate macrophage infiltration and cytokine production but also promote a pro-resolving macrophage phenotype. In this review, we discuss the homeostatic functions of SPMs acting directly on macrophages on various levels, towards the resolution of inflammation. Moreover, we address the molecular events that link the lipid mediators with COVID-19 severity and discuss the clinical potentials of SPMs in COVID-19 immunotherapeutics.

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Roles of Specialized Pro-Resolving Lipid Mediators in Autophagy and Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms21186637 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6637 ◽

Cited By ~ 1

Author(s):

Antonio Recchiuti ◽

Elisa Isopi ◽

Mario Romano ◽

Domenico Mattoscio

Keyword(s):

Inflammatory Response ◽

Cytokine Production ◽

Lipid Mediators ◽

Tissue Homeostasis ◽

Leukocyte Infiltration ◽

Catabolic Pathway ◽

Resolution Of Inflammation ◽

Endogenous Lipid ◽

Inflammation Resolution ◽

Cellular Components

Autophagy is a catabolic pathway that accounts for degradation and recycling of cellular components to extend cell survival under stress conditions. In addition to this prominent role, recent evidence indicates that autophagy is crucially involved in the regulation of the inflammatory response, a tightly controlled process aimed at clearing the inflammatory stimulus and restoring tissue homeostasis. To be efficient and beneficial to the host, inflammation should be controlled by a resolution program, since uncontrolled inflammation is the underlying cause of many pathologies. Resolution of inflammation is an active process mediated by a variety of mediators, including the so-called specialized pro-resolving lipid mediators (SPMs), a family of endogenous lipid autacoids known to regulate leukocyte infiltration and activities, and counterbalance cytokine production. Recently, regulation of autophagic mechanisms by these mediators has emerged, uncovering unappreciated connections between inflammation resolution and autophagy. Here, we summarize mechanisms of autophagy and resolution, focusing on the contribution of autophagy in sustaining paradigmatic examples of chronic inflammatory disorders. Then, we discuss the evidence that SPMs can restore dysregulated autophagy, hypothesizing that resolution of inflammation could represent an innovative approach to modulate autophagy and its impact on the inflammatory response.

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Lipodystrophy and obesity are associated with decreased number of T cells with regulatory function and pro-inflammatory macrophage phenotype

International Journal of Obesity ◽

10.1038/ijo.2017.163 ◽

2017 ◽

Vol 41 (11) ◽

pp. 1676-1684 ◽

Cited By ~ 6

Author(s):

S Berger ◽

G Ceccarini ◽

G Scabia ◽

I Barone ◽

C Pelosini ◽

...

Keyword(s):

T Cells ◽

Regulatory Function ◽

Macrophage Phenotype ◽

Inflammatory Macrophage

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LGK974 suppresses lipopolysaccharide-induced endotoxemia in mice by modulating the crosstalk between the Wnt/β-catenin and NF-κB pathways

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00577-z ◽

2021 ◽

Vol 53 (3) ◽

pp. 407-421

Author(s):

Jaewoong Jang ◽

Jaewon Song ◽

Hyunji Lee ◽

Inae Sim ◽

Young V. Kwon ◽

...

Keyword(s):

Animal Model ◽

Survival Rate ◽

Wnt Pathway ◽

Cytokine Production ◽

Cytokine Storm ◽

Plasma Cytokine ◽

Gram Negative ◽

Multiple Organs ◽

Expression Of Genes ◽

Cytokine Levels

AbstractEndotoxemia, a type of sepsis caused by gram-negative bacterial endotoxin [i.e., lipopolysaccharide (LPS)], is associated with manifestations such as cytokine storm; failure of multiple organs, including the liver; and a high mortality rate. We investigated the effect and mechanism of action of LGK974, a Wnt signaling inhibitor, in mice with LPS-induced endotoxemia, an animal model of sepsis. LGK974 significantly and dose-dependently increased the survival rate and reduced plasma cytokine levels in mice with LPS-induced endotoxemia. Transcriptome analysis of liver tissues revealed significant changes in the expression of genes associated with the Wnt pathway as well as cytokine and NF-κB signaling during endotoxemia. LGK974 treatment suppressed the activation of NF-κB signaling and cytokine expression as well as the Wnt/β-catenin pathway in the livers of endotoxemic mice. Coimmunoprecipitation of phospho-IκB and β-transducin repeat-containing protein (β-TrCP) was increased in the livers of endotoxemic mice but was reduced by LGK974 treatment. Moreover, LGK974 treatment decreased the coimmunoprecipitation and colocalization of β-catenin and NF-κB, which were elevated in the livers of endotoxemic mice. Our results reveal crosstalk between the Wnt/β-catenin and NF-κB pathways via interactions between β-TrCP and phospho-IκB and between β-catenin and NF-κB during endotoxemia. The results of this study strongly suggest that the crosstalk between the Wnt/β-catenin and NF-κB pathways contributes to the mutual activation of these two pathways during endotoxemia, which results in amplified cytokine production, liver damage and death, and that LGK974 suppresses this vicious amplification cycle by reducing the crosstalk between these two pathways.

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Endogenous Receptor Agonists: Resolving Inflammation

The Scientific World JOURNAL ◽

10.1100/tsw.2007.188 ◽

2007 ◽

Vol 7 ◽

pp. 1440-1462 ◽

Cited By ~ 30

Author(s):

Gerhard Bannenberg ◽

Makoto Arita ◽

Charles N. Serhan

Keyword(s):

Fatty Acids ◽

Essential Fatty Acids ◽

Tissue Level ◽

Lipid Mediators ◽

Recent Advances ◽

Molecular Events ◽

Inflammation Resolution ◽

Specific Lipid ◽

Chemical Mediators

Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and ω-3 polyunsaturated fatty acids (PUFA)–derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS–based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.

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Implications of lipid raft disintegration: Enhanced anti-inflammatory macrophage phenotype

Surgery ◽

10.1016/j.surg.2004.04.009 ◽

2004 ◽

Vol 136 (2) ◽

pp. 169-175 ◽

Cited By ~ 25

Author(s):

Joseph Cuschieri

Keyword(s):

Lipid Raft ◽

Macrophage Phenotype ◽

Anti Inflammatory ◽

Inflammatory Macrophage

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Probiotic Conditioned Media Induces an Anti-Inflammatory Macrophage Phenotype In Vivo and In Vitro

Gastroenterology ◽

10.1016/s0016-5085(11)60074-7 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-19

Author(s):

Michelle Taylor ◽

Vandana Gambhir ◽

Curtis Noordhof ◽

Oliver Jones ◽

Shu-Mei He ◽

...

Keyword(s):

Conditioned Media ◽

Macrophage Phenotype ◽

Anti Inflammatory ◽

Inflammatory Macrophage

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Macrophage-associated pro-inflammatory state in human islets from obese individuals

Nutrition and Diabetes ◽

10.1038/s41387-019-0103-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Wei He ◽

Ting Yuan ◽

Kathrin Maedler

Keyword(s):

Inflammatory Cytokines ◽

Macrophage Polarization ◽

Human Islets ◽

Macrophage Phenotype ◽

Inflammatory State ◽

Obese Control ◽

Inflammatory Macrophages ◽

Inflammatory Macrophage ◽

Pro Inflammatory Cytokines

AbstractObesity is associated with inflammatory macrophages in insulin responsive tissues and the resulting inflammatory response is a major contributor to insulin resistance. In insulin-producing pancreatic islets, the intra-islet accumulation of macrophages is observed in patients of type 2 diabetes (T2D), but such has not been investigated in obese individuals. Here, we show that pro-inflammatory cytokines (IL-1β, IL-6, and TNF), anti-inflammatory cytokines (IL-10 and TGF-β) and macrophage polarization markers (CD11c, CD163, and NOS2) were expressed in isolated human islets from non-diabetic donors. Clodronate-mediated depletion of resident macrophages revealed expression of IL1B and IL10 mostly from macrophages, while IL6, TNF, and TGFB1 came largely from a non-macrophage origin in human islets. NOS2 expression came exclusively from non-macrophage cells in non-obese individuals, while it originated also from macrophages in obese donors. Macrophage marker expression of CD68, CD163, and ITGAX was unchanged in islets of non-obese control and obese cohorts. In contrast, IL1B and NOS2 were significantly increased in islets from obese, compared to non-obese individuals, implying a more inflammatory macrophage phenotype in islets in obesity. Our study shows elevated macrophage-associated inflammation in human islets in obesity, which could be an initiating factor to the pro-inflammatory intra-islet milieu and contribute to the higher susceptibility to T2D in obese individuals.

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Blockade of 4-1BB and 4-1BBL Interaction Reduces Obesity-Induced Skeletal Muscle Inflammation

Mediators of Inflammation ◽

10.1155/2013/865159 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Ngoc Hoan Le ◽

Chu-Sook Kim ◽

Thai Hien Tu ◽

Hye-Sun Choi ◽

Byung-Sam Kim ◽

...

Keyword(s):

Skeletal Muscle ◽

Inflammatory Cytokines ◽

High Fat Diet ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Muscle Cells ◽

Macrophage Infiltration ◽

High Fat ◽

Inflammatory Cytokine Production ◽

Muscle Inflammation

Obesity-induced skeletal muscle inflammation is characterized by increased macrophage infiltration and inflammatory cytokine production. In this study, we investigated whether 4-1BB, a member of the TNF receptor superfamily (TNFRSF9) that provides inflammatory signals, participates in obesity-induced skeletal muscle inflammation. Expression of the 4-1BB gene, accompanied by increased levels of inflammatory cytokines, was markedly upregulated in the skeletal muscle of obese mice fed a high-fat diet, in muscle cells treated with obesity factors, and in cocultured muscle cells/macrophages. In vitro stimulation of 4-1BB with agonistic antibody increased inflammatory cytokine levels in TNFα-pretreated muscle cells, and this effect was absent in cells derived from 4-1BB-deficient mice. Conversely, disruption of the interaction between 4-1BB and its ligand (4-1BBL) with blocking antibody decreased the release of inflammatory cytokines from cocultured muscle cells/macrophages. Moreover, deficiency of 4-1BB markedly reduced macrophage infiltration and inflammatory cytokine production in the skeletal muscle of mice fed a high-fat diet. These findings indicate that 4-1BB mediates the inflammatory responses in obese skeletal muscle by interacting with its ligand 4-1BBL on macrophages. Therefore, 4-1BB and 4-1BBL may be useful targets for prevention of obesity-induced inflammation in skeletal muscle.

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Fine-tuning nucleophosmin in macrophage differentiation and activation

Blood ◽

10.1182/blood-2011-03-341255 ◽

2011 ◽

Vol 118 (17) ◽

pp. 4694-4704 ◽

Cited By ~ 21

Author(s):

Leslie Guery ◽

Naïma Benikhlef ◽

Thomas Gautier ◽

Catherine Paul ◽

Gaetan Jego ◽

...

Keyword(s):

Cytokine Production ◽

Gene Promoter ◽

Full Length ◽

Fine Tuning ◽

Dual Function ◽

Macrophage Phenotype ◽

Blood Monocytes ◽

Inflammatory Cytokine Production ◽

Inflammatory Stimuli ◽

Genes Encoding

Abstract M-CSF–driven differentiation of peripheral blood monocytes is one of the sources of tissue macrophages. In humans and mice, the differentiation process involves the activation of caspases that cleave a limited number of proteins. One of these proteins is nucleophosmin (NPM1), a multifunctional and ubiquitous protein. Here, we show that caspases activated in monocytes exposed to M-CSF cleave NPM1 at D213 to generate a 30-kDa N-terminal fragment. The protein is further cleaved into a 20-kDa fragment, which involves cathepsin B. NPM1 fragments contribute to the limited motility, migration, and phagocytosis capabilities of resting macrophages. Their activation with lipopolysaccharides inhibits proteolytic processes and restores expression of the full-length protein that negatively regulates the transcription of genes encoding inflammatory cytokines (eg, NPM1 is recruited with NF-κB on the MCP1 gene promoter to decrease its transcription). In mice with heterozygous npm gene deletion, cytokine production in response to lipopolysaccharides, including CXCL1 (KC), MCP1, and MIP2, is dramatically enhanced. These results indicate a dual function of NPM1 in M-CSF–differentiated macrophages. Proteolysis of the protein participates in the establishment of a mature macrophage phenotype. In response to inflammatory stimuli, the full-length protein negatively regulates inflammatory cytokine production.

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