Benznidazole Anti-Inflammatory Effects in Murine Cardiomyocytes and Macrophages Are Mediated by Class I PI3Kδ

Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, leads to parasite clearance in the early stages of infection and contributes to immunomodulation. In addition to its parasiticidal effect, Bzl inhibits the NF-κB pathway. In this regard, we have previously described that this occurs through IL-10/STAT3/SOCS3 pathway. PI3K pathway is involved in the regulation of the immune system by inhibiting NF-κB pathway through STAT3. In this work, the participation of PI3K in the immunomodulatory effects of Bzl in cardiac and immune cells, the main targets of Chagas disease, was further studied. For that, we use a murine primary cardiomyocyte culture and a monocyte/macrophage cell line (RAW 264.7), stimulated with LPS in presence of LY294002, an inhibitor of PI3K. Under these conditions, Bzl could neither increase SOCS3 expression nor inhibit the NOS2 mRNA expression and the release of NOx, both in cardiomyocytes and macrophages. Macrophages are crucial in the development of Chronic Chagas Cardiomyopathy. Thus, to deepen our understanding of how Bzl acts, the expression profile of M1-M2 macrophage markers was evaluated. Bzl inhibited the release of NOx (M1 marker) and increased the expression of Arginase I (M2 marker) and a negative correlation was found between them. Besides, LPS increased the expression of pro-inflammatory cytokines. Bzl treatment not only inhibited this effect but also increased the expression of typical M2-macrophage markers like Mannose Receptor, TGF-β, and VEGF-A. Moreover, Bzl increased the expression of PPAR-γ and PPAR-α, known as key regulators of macrophage polarization. PI3K directly regulates M1-to-M2 macrophage polarization. Since p110δ, catalytic subunit of PI3Kδ, is highly expressed in immune cells, experiments were carried out in presence of CAL-101, a specific inhibitor of this subunit. Under this condition, Bzl could neither increase SOCS3 expression nor inhibit NF-κB pathway. Moreover, Bzl not only failed to inhibit the expression of pro-inflammatory cytokines (M1 markers) but also could not increase M2 markers. Taken together these results demonstrate, for the first time, that the anti-inflammatory effect of Bzl depends on PI3K activity in a cell line of murine macrophages and in primary culture of neonatal cardiomyocytes. Furthermore, Bzl-mediated increase expression of M2-macrophage markers involves the participation of the p110δ catalytic subunit of PI3Kδ.

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Decursinol Angelate Inhibits LPS-Induced Macrophage Polarization through Modulation of the NFκB and MAPK Signaling Pathways

Molecules ◽

10.3390/molecules23081880 ◽

2018 ◽

Vol 23 (8) ◽

pp. 1880 ◽

Cited By ~ 15

Author(s):

Salman Islam ◽

Jung Lee ◽

Adeeb Shehzad ◽

Eun-Mi Ahn ◽

You Lee ◽

...

Keyword(s):

Map Kinase ◽

Signaling Pathways ◽

Inflammatory Cytokines ◽

Macrophage Polarization ◽

Raw 264.7 Cells ◽

M2 Macrophage ◽

Raw 264.7 ◽

Decursinol Angelate ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Inflammation is considered the root cause of various inflammatory diseases, including cancers. Decursinol angelate (DA), a pyranocoumarin compound obtained from the roots of Angelica gigas, has been reported to exhibit potent anti-inflammatory effects. In this study, the anti-inflammatory effects of DA on the MAP kinase and NFκB signaling pathways and the expression of pro-inflammatory cytokines were investigated in phorbol 12-myristate 13-acetate (PMA)-activated human promyelocytic leukemia (HL-60) and lipopolysaccharide (LPS)-stimulated macrophage (Raw 264.7) cell lines. PMA induced the activation of the MAP kinase-NFκB pathway and the production of pro-inflammatory cytokines in differentiated monocytes. Treatment with DA inhibited the activation of MAP kinases and the translocation of NFκB, and decreased the expression and exogenous secretion of IL-1β and IL-6. Furthermore, LPS-stimulated Raw 264.7 cells were found to have increased expression of M1 macrophage-associated markers, such as NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS), and the M2 macrophage-associated marker CD11b. LPS also activated pro-inflammatory cytokines and Erk-NFκB. Treatment with DA suppressed LPS-induced macrophage polarization and the inflammatory response by blocking Raf-ERK and the translocation of NFκB in Raw 264.7 cells. Treatment with DA also inhibited the expression of pro-inflammatory cytokines, such as IL-1β and IL-6, NOX, and iNOS in Raw 264.7 cells. These results suggest that DA has the potential to inhibit macrophage polarization and inflammation by blocking the activation of pro-inflammatory signals. These anti-inflammatory effects of DA may contribute to its potential use as a therapeutic strategy against various inflammation-induced cancers.

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BMP-7 attenuates adverse cardiac remodeling mediated through M2 macrophages in prediabetic cardiomyopathy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00367.2014 ◽

2014 ◽

Vol 307 (5) ◽

pp. H762-H772 ◽

Cited By ~ 24

Author(s):

Princess Urbina ◽

Dinender K. Singla

Keyword(s):

Cardiac Function ◽

Inflammatory Cytokines ◽

Cardiac Remodeling ◽

Therapeutic Potential ◽

M2 Macrophage ◽

M2 Macrophages ◽

Citrate Buffer ◽

Morphogenetic Protein ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

The main objective of this study was to determine whether or not monocyte infiltration occurs in the prediabetic (PD) heart and its role in PD cardiomyopathy. We hypothesized that the PD heart is significantly populated with monocytes and that bone morphogenetic protein (BMP)-7, a novel mediator of monocyte polarization, activates infiltrated monocytes into anti-inflammatory M2 macrophages, thereby inhibiting apoptosis and fibrosis and improving cardiac function. C57Bl6 mice were assigned to control, PD, or PD + BMP-7 groups. PD and PD + BMP-7 groups were administered streptozotocin (50 mg/kg), whereas control animals received sodium citrate buffer. Afterward, the PD + BMP-7 group was administered BMP-7 (200 μg/kg) for 3 days. Our data showed significantly increased infiltrated monocytes and associated pro-inflammatory cytokines, adverse cardiac remodeling, and heart dysfunction in the PD group ( P < 0.05). Interestingly, M2 macrophage differentiation and associated anti-inflammatory cytokines were enhanced and there were reduced adverse cardiac remodeling and improved cardiac function in the PD + BMP-7 group ( P < 0.05). In conclusion, our data suggest that PD cardiomyopathy is associated with increased monocyte infiltration and released proinflammatory cytokines, which contributes to adverse cardiac remodeling and cardiac dysfunction. Moreover, we report that BMP-7 possesses novel therapeutic potential in its ability to differentiate monocytes into M2 macrophages and confer cardiac protection in the PD heart.

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Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages

Biochemical Journal ◽

10.1042/bcj20160646 ◽

2017 ◽

Vol 474 (4) ◽

pp. 521-537 ◽

Cited By ~ 18

Author(s):

Nicola J. Darling ◽

Rachel Toth ◽

J. Simon C. Arthur ◽

Kristopher Clark

Keyword(s):

Inflammatory Cytokines ◽

Drug Targets ◽

Macrophage Polarization ◽

Macrophage Phenotype ◽

Integral Role ◽

Inflammatory Phenotype ◽

Low Levels ◽

Anti Inflammatory ◽

Factor Α ◽

Pro Inflammatory Cytokines

The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown. To address this question, we developed knock-in (KI) mice for SIK1, SIK2 and SIK3, in which we introduced a mutation that renders the enzymes catalytically inactive. Characterization of primary macrophages from the single and double KI mice established that all three SIK isoforms, and in particular SIK2 and SIK3, contribute to macrophage polarization. Moreover, we discovered that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhanced the production of IL-10 compared with their inhibition in mature macrophages. Interestingly, macrophages differentiated in the presence of SIK inhibitors, MRT199665 and HG-9-91-01, still produced very large amounts of IL-10, but very low levels of pro-inflammatory cytokines, even after the SIKs had been reactivated by removal of the drugs. Our data highlight an integral role for SIK2 and SIK3 in innate immunity by preventing the differentiation of macrophages into a potent and stable anti-inflammatory phenotype.

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Abstract 492: Resolvin D2 Inhibits Murine Abdominal Aortic Aneurysm and Increases M2 Macrophage Differentiation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.492 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Nicolas H Pope ◽

Morgan Salmon ◽

Michael S Conte ◽

Gorav Ailawadi ◽

Gilbert R Upchurch

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Inflammatory Cytokines ◽

Macrophage Polarization ◽

Neointimal Hyperplasia ◽

M2 Macrophage ◽

M2 Macrophages ◽

Cytokine Analysis ◽

Abdominal Aortic ◽

Pro Inflammatory Cytokines

Objectives: Macrophages are critical to abdominal aortic aneurysm (AAA) formation; however, the role of anti-inflammatory M2 macrophages is not known. Resolvins have been shown to play a protective role in neointimal hyperplasia; however, their role in AAA has not been established. We hypothesized that treatment with Resolvin D2 (RvD2) attenuates murine AAA formation through alterations in macrophage polarization and cytokine expression. Methods: Male C57/B6 mice (n=9/group) of 8-12 weeks of age received RvD2 (100 ng/kg/treatment) or vehicle only every third day beginning three days prior to abdominal aortic perfusion with elastase. Aortas were harvested 14 days following elastase perfusion. Cytokine analysis (n=5/group) or confocal microscopy (n=4/group) was performed. Cytokine profiles were analyzed using a murine antibody array. To determine the effect of RvD2 on macrophage polarization, confocal staining for macrophages (Mac2), M1 (MCP-1) and M2 (Arg-1) macrophage subtypes, α-actin and 4',6-diamidino-2-phenylindole (DAPI) was utilized. Results: Mean aortic dilation was 96.23 % (± 13.07 %) for vehicle treated and 56.58% (± 9.69%) for RvD2 treated mice (p<0.0001). Pro-inflammatory cytokines CXCL-10, IL-1β, TIMP-1 and MCP-1 were significantly elevated in control as compared to RvD2 treated animals. Confocal histology demonstrated a prevalence of M2 macrophages within the aortic media in mice treated with RvD2 (Figure 1). Conclusions: Resolvin D2 exhibits a potent protective effect against experimental AAA formation. Treatment with RvD2 significantly influences macrophage polarization and decreases several important pro-inflammatory cytokines. Resolvins and the alteration of macrophage polarization represent potential future targets for prevention of AAA.

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HIMF deletion ameliorates acute myocardial ischemic injury by promoting macrophage transformation to reparative subtype

Basic Research in Cardiology ◽

10.1007/s00395-021-00867-7 ◽

2021 ◽

Vol 116 (1) ◽

Author(s):

Yanjiao Li ◽

Min Dong ◽

Qing Wang ◽

Santosh Kumar ◽

Rui Zhang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Myocardial Infarct ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Myocardial Infarct Size ◽

Myocardial Repair ◽

Stat3 Signaling ◽

Gene Ablation ◽

M1 Macrophage ◽

Pro Inflammatory Cytokines

AbstractAppropriately manipulating macrophage M1/M2 phenotypic transition is a promising therapeutic strategy for tissue repair after myocardial infarction (MI). Here we showed that gene ablation of hypoxia-induced mitogenic factor (HIMF) in mice (Himf−/− and HIMFflox/flox;Lyz2-Cre) attenuated M1 macrophage-dominated inflammatory response and promoted M2 macrophage accumulation in infarcted hearts. This in turn reduced myocardial infarct size and improved cardiac function after MI. Correspondingly, expression of HIMF in macrophages induced expression of pro-inflammatory cytokines; the culturing medium of HIMF-overexpressing macrophages impaired the cardiac fibroblast viability and function. Furthermore, macrophage HIMF was found to up-regulate C/EBP-homologous protein (CHOP) expression, which exaggerated the release of pro-inflammatory cytokines via activating signal transducer of activator of transcription 1 (STAT1) and 3 (STAT3) signaling. Together these data suggested that HIMF promotes M1-type and prohibits M2-type macrophage polarization by activating the CHOP–STAT1/STAT3 signaling pathway to negatively regulate myocardial repair. HIMF might thus constitute a novel target to treat MI.

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Effect of switching glatiramer acetate formulation from 20 mg daily to 40 mg three times weekly on immune function in multiple sclerosis

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/20552173211032323 ◽

2021 ◽

Vol 7 (3) ◽

pp. 205521732110323

Author(s):

Kouichi Ito ◽

Naoko Ito ◽

Sudhir K Yadav ◽

Shradha Suresh ◽

Yong Lin ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Immune Cells ◽

Immunological Parameters ◽

Gm Csf ◽

Tnf Α ◽

Annualized Relapse Rate ◽

Ifn Γ ◽

Anti Inflammatory ◽

The Difference ◽

Pro Inflammatory Cytokines

Background Many RRMS patients who had been treated for over 20 years with GA 20 mg/ml daily (GA20) switched to 40 mg/ml three times-a-week (GA40) to reduce injection-related adverse events. Although GA40 is as effective as GA20 in reducing annualized relapse rate and MRI activity, it remains unknown how switching to GA40 from GA20 affects the development of pathogenic and regulatory immune cells. Objective To investigate the difference in immunological parameters in response to GA20 and GA40 treatments. Methods We analyzed five pro-inflammatory cytokines (IL-1β, IL-23, IL-12, IL-18, TNF-α), and three anti-inflammatory/regulatory cytokines (IL-10, IL-13, and IL-27) in serum. In addition, we analyzed six cytokines (IFN-γ, IL-17A, GM-CSF, IL-10, IL-6, and IL-27) in cultured PBMC supernatants. The development of Th1, Th17, Foxp3 Tregs, M1-like, and M2-like macrophages were examined by flow cytometry. Samples were analyzed before and 12 months post switching to GA40 or GA20. Results Pro- and anti-inflammatory cytokines were comparable between the GA40 and GA20 groups. Development of Th1, Th17, M1-like macrophages, M2-like macrophages, and Foxp3 Tregs was also comparable between the two groups. Conclusions The immunological parameters measured in RRMS patients treated with GA40 three times weekly are largely comparable to those given daily GA20 treatment.

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Primary human monocytes differentiate into M2 macrophages and involve Notch-1 pathway

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0319 ◽

2017 ◽

Vol 95 (3) ◽

pp. 288-294 ◽

Cited By ~ 15

Author(s):

Dinender K. Singla ◽

Jing Wang ◽

Reetu Singla

Keyword(s):

Signaling Pathway ◽

Inflammatory Cytokines ◽

M2 Macrophage ◽

Human Monocytes ◽

M2 Macrophages ◽

Notch 1 ◽

Macrophage Differentiation ◽

Arginase 1 ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

The current study investigates whether inhibiting the Notch-1 signaling pathway in primary human monocytes enhances M2 macrophage differentiation. We generated a primary human monocyte cell culture model to understand the effect of the Notch-1 signaling pathway. Monocytes were treated with Notch-1 inhibitors DAPT or siRNA. Our data show that there was a significant increase in the M1 macrophage population demonstrated by iNOS marker in the primary human monocytes treated with apoptotic-conditioned medium (ACM). Next, the levels of pro-inflammatory cytokines IL-6 and MCP-1, as well as TNF-α, increased in ACM media (p < 0.05). Furthermore, M1 macrophages and pro-inflammatory cytokines were reduced following DAPT or siRNA treatment. Comparatively, there was a significant increase in M2 macrophages, as demonstrated by an increase in CD206 and arginase-1 positive cells treated with DAPT or siRNA (p < 0.05). Furthermore, a significant increase in the associated anti-inflammatory cytokines IL-10 and IL-1RA was also observed with respect to control groups (p < 0.05). We conclude that blocking the Notch-1 pathway with DAPT or siRNA attenuates pro-inflammatory cytokines, enhances M2 macrophage differentiation, and increases anti-inflammatory cytokines in primary human monocytes. As a result, Notch-1 pathway inhibition has potential therapeutic applications of inflammatory disease.

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Targeting the NF-κb-Dependent HIF-1β Pathway Reprograms Macrophage Polarization Induced By Oxidized LDL

Blood ◽

10.1182/blood.v130.suppl_1.993.993 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 993-993

Author(s):

Jin Fengyan ◽

Wang Xue ◽

Wu Jiang ◽

Yun Dai

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Cell Line ◽

Inflammatory Cytokines ◽

Macrophage Polarization ◽

Human Macrophages ◽

M2 Polarization ◽

M1 Polarization ◽

Anti Inflammatory ◽

Hif Pathway

Abstract Introduction: Plasticity is one of the hallmarks of macrophages, an essential component of innate and adaptive immunity. In response to various stimuli, macrophages can differentiate or polarize to either pro-inflammatory M1 or anti-inflammatory M2 phenotype, which determines whether inflammation is initiated and promoted or terminated and resolved. Of note, the phenotype of polarized M1-M2 macrophages may be reversed in certain circumstances, providing an opportunity to treat inflammatory disorders (e.g., atherosclerosis) and inflammation-related diseases (e.g., cancer) by targeting macrophage polarization. Emerging evidence supports that transcriptional regulation play an important role in polarization and function of macrophages via reprogramming expression of pro- versus anti-inflammatory genes. However, despite well-established cross-talk between two major transcriptional factors, NF-κB and hypoxia-inducible factor (HIF), it remains unclear whether NF-κB interacts with HIFs (particularly HIF-1β, a regulatory subunit of the active HIF complex) in reprogramming macrophages. Here, we investigated the mechanism underlying macrophage activation induced by oxidized low density lipoprotein (oxLDL), a central event of uncontrolled inflammation in atherosclerosis. Materials and Methods: The murine macrophage cell line RAW264.7 and human THP-1 cell line-derived macrophages were employed. After exposed to oxLDL, cells were analyzed by qPCR, Western blot, flow cytometry (Cytometric Bead Array, CBA), and ELISA analyses to monitor expression of M1 and M2 markers and related cytokines, as well as activation of the NF-κB and HIF pathways. The shRNA approach was used to knock down expression of target genes for functional evaluation. The findings from in vitro experiments involving cell lines were then validated in primary samples obtained from healthy donors (n = 10) and patients with coronary heart disease (n = 22) and stroke (n = 11). Results: Exposure to oxLDL triggered M1 polarization of murine and human macrophages, characterized by expression of iNOS and robust production of M1 pro-inflammatory cytokines (e.g., TNF-α, MCP-1, IL-1β, IL-6) but not M2 anti-inflammatory cytokines (e.g., IL-10, TGF-β). In contrast, protein level of the M2 marker Arg1 was clearly decreased after treated with oxLDL. Notably, exposure of macrophages to oxLDL resulted in markedly increased expression of HIF-1α and -1β, in association with activation of both canonical and non-canonical NF-κB pathways. Functionally, whereas inhibition of NF-κB activation by the IKK inhibitor parthenolide almost completely prevented M1 polarization and promoted M2 polarization, knockdown of HIF-1β by shRNA also largely reversed macrophage polarization from M1 to M2 after exposed to oxLDL. These results were confirmed in human macrophages differentiated by PMA from primary peripheral blood monocytes obtained from patients with coronary heart disease or ischemic stroke, and normal donors. These events were accompanied by a clear reversal of oxLDL-induced morphological changes of macrophages. Mechanistically, inhibition of NF-κB activation dramatically diminished expression of HIF-1α and -1β induced by oxLDL. However, while shRNA knockdown of HIF-1β sharply blocked HIF-1α expression in macrophages exposed to oxLDL, it failed to impair activation of NF-κB. These findings indicate that oxLDL-induced HIF-1β expression is dependent on NF-κB activation, which in turn activates the HIF pathway via HIF-1α up-regulation probably by stabilizing HIF-1α protein. Conclusion: HIF-1β (encoded by ARNT) is identified for the first time as a novel target that reprograms M1-M2 polarization of macrophages, at least after exposure to oxLDL, a risk factor of atherosclerosis. HIF-1β is further demonstrated to act as downstream of NF-κB to induce activation of the HIF pathway. Importantly, these findings suggest that HIF-1β might serve as a therapeutic target for the treatment of inflammatory disorders such as atherosclerosis, and probably immune diseases and cancer as well. Disclosures No relevant conflicts of interest to declare.

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The role of macrophage polarization and associated mechanisms in regulating the anti-inflammatory action of acupuncture: a literature review and perspectives

Chinese Medicine ◽

10.1186/s13020-021-00466-7 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Jiaqi Wang ◽

Shanshan Lu ◽

Fuming Yang ◽

Yi Guo ◽

Zelin Chen ◽

...

Keyword(s):

Macrophage Polarization ◽

Scientific Basis ◽

M2 Macrophage ◽

Extrinsic Factors ◽

Therapeutic Goals ◽

Tissue Microenvironment ◽

Inflammatory Conditions ◽

Cytokine Levels ◽

Anti Inflammatory ◽

Inflammatory Action

AbstractAcupuncture is used in the treatment of a variety of inflammatory conditions and diseases. However, the mechanisms of its anti-inflammatory action are complex and have not been systematically investigated. Macrophages are key components of the innate immune system, thus, balancing the M1/M2 macrophage ratio and modulating cytokine levels in the inflammatory environment may be desirable therapeutic goals. Evidence has shown that acupuncture has anti-inflammatory actions that affect multiple body systems, including the immune, locomotory, endocrine, nervous, digestive, and respiratory systems, by downregulating pro-inflammatory M1 and upregulating anti-inflammatory M2 macrophages, as well as by modulating associated cytokine secretion. Macrophage polarization is controlled by the interlocking pathways of extrinsic factors, the local tissue microenvironment, and the neural-endocrine-immune systems. It has been suggested that polarization of T lymphocytes and cytokine secretions resulting in modulation of the autonomic nervous system and the hypothalamic–pituitary–adrenal axis, may be upstream mechanisms of acupuncture-induced macrophage polarization. We further propose that macrophage polarization could be the principal pathway involved in acupuncture immune regulation and provide the scientific basis for the clinical application of acupuncture in inflammatory conditions.

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Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽

10.3390/biom11050653 ◽

2021 ◽

Vol 11 (5) ◽

pp. 653

Author(s):

Seth O. Asiedu ◽

Samuel K. Kwofie ◽

Emmanuel Broni ◽

Michael D. Wilson

Keyword(s):

Molecular Docking ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Binding Energies ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Activity ◽

Computational Techniques ◽

Cytokine Storm ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

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