Macrophage TLR4 and PAR2 Signaling: Role in Regulating Vascular Inflammatory Injury and Repair

Rayees, Sheikh; Rochford, Ian; Joshi, Jagdish Chandra; Joshi, Brijendra Kumar; Banerjee, Sumanta; Mehta, Dolly

doi:10.3389/fimmu.2020.02091

Cited by 44 publications

(39 citation statements)

References 184 publications

(232 reference statements)

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“…LPS contains lipid A, a non-repeating “core” of oligosaccharide that has the endotoxic properties and is recognized by its Toll Like Receptor 4 (TLR4). It was known that TLR4 is expressed on the cell surface of macrophages and the activation of TLR4 mediates the inflammatory response in lung macrophages [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

Recombinant Antigen of Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2) Promotes M1 Repolarization of Porcine Alveolar Macrophages and Th1 Type Response

Wahyuningtyas

Lai

et al. 2021

Vaccines

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The polarization status of porcine alveolar macrophages (PAMs) determines the infectivity of porcine reproductive and respiratory syndrome virus (PRRSV). PRRSV infection skews macrophage polarization toward an M2 phenotype, followed by T-cells inactivation. CD163, one of the scavenger receptors of M2 macrophages, has been described as a putative receptor for PRRSV. In this study, we examined two types of PRRSV-2-derived recombinant antigens, A1 (g6Ld10T) and A2 (lipo-M5Nt), for their ability to mediate PAM polarization and T helper (Th1) response. A1 and A2 were composed of different combination of ORF5, ORF6, and ORF7 in full or partial length. To enhance the adaptive immunity, they were conjugated with T cells epitopes or lipidated elements, respectively. Our results showed that CD163+ expression on PAMs significantly decreased after being challenged with A1 but not A2, followed by a significant increase in pro-inflammatory genes (TNF-α, IL-6, and IL-12). In addition, next generation sequencing (NGS) data show an increase in T-cell receptor signaling in PAMs challenged with A1. Using a co-culture system, PAMs challenged with A1 can induce Th1 activation by boosting IFN-γ and IL-12 secretion and TNF-α expression. In terms of innate and T-cell-mediated immunity, we conclude that A1 is regarded as a potential vaccine for immunization against PRRSV infection due to its ability to reverse the polarization status of PAMs toward pro-inflammatory phenotypes, which in turn reduces CD163 expression for viral entry and increases immunomodulation for Th1-type response.

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Section: Resultsmentioning

confidence: 99%

Recombinant Antigen of Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2) Promotes M1 Repolarization of Porcine Alveolar Macrophages and Th1 Type Response

Wahyuningtyas

Lai

et al. 2021

Vaccines

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“…NRH supplementation induced phosphorylation of p65, a hallmark of NFkB activation, indicating activation of this pathway. The NF-kB pathway is one of the main pathways involved in inflammation and cytokine production in macrophages, and pro-inflammatory stimuli such as LPS are potent activators of this pathway (49). Thus, NRH and LPS might activate similar pro-inflammatory pathways in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Dihydronicotinamide Riboside Is a Potent NAD+ Precursor Promoting a Pro-Inflammatory Phenotype in Macrophages

Chini

Peclat²,

Gomez³

et al. 2022

Front. Immunol.

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Nicotinamide adenine dinucleotide (NAD) metabolism plays an important role in the regulation of immune function. However, a complete picture of how NAD, its metabolites, precursors, and metabolizing enzymes work together in regulating immune function and inflammatory diseases is still not fully understood. Surprisingly, few studies have compared the effect of different forms of vitamin B3 on cellular functions. Therefore, we investigated the role of NAD boosting in the regulation of macrophage activation and function using different NAD precursors supplementation. We compared nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and nicotinamide (NAM) supplementation, with the recently described potent NAD precursor NRH. Our results show that only NRH supplementation strongly increased NAD+ levels in both bone marrow-derived and THP-1 macrophages. Importantly, NRH supplementation activated a pro-inflammatory phenotype in resting macrophages, inducing gene expression of several cytokines, chemokines, and enzymes. NRH also potentiated the effect of lipopolysaccharide (LPS) on macrophage activation and cytokine gene expression, suggesting that potent NAD+ precursors can promote inflammation in macrophages. The effect of NRH in NAD+ boosting and gene expression was blocked by inhibitors of adenosine kinase, equilibrative nucleoside transporters (ENT), and IκB kinase (IKK). Interestingly, the IKK inhibitor, BMS-345541, blocked the mRNA expression of several enzymes and transporters involved in the NAD boosting effect of NRH, indicating that IKK is also a regulator of NAD metabolism. In conclusion, NAD precursors such as NRH may be important tools to understand the role of NAD and NADH metabolism in the inflammatory process of other immune cells, and to reprogram immune cells to a pro-inflammatory phenotype, such as the M2 to M1 switch in macrophage reprogramming, in the cancer microenvironment.

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“…Our results are consistent with the findings from previous studies ( Li X. et al, 2020 ; Yang et al, 2020 ). When TLR4 is activated, it can regulate the expression of various inflammatory mediators and cytokines through transmembrane signaling, and initiate defense and immune regulation ( Rahimifard et al, 2017 ; Rayees et al, 2020 ). Studies have shown that TLR4-mediated inflammatory response plays an important role in heart, lung, liver, and cerebral I/R injury ( Rayees et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…When TLR4 is activated, it can regulate the expression of various inflammatory mediators and cytokines through transmembrane signaling, and initiate defense and immune regulation ( Rahimifard et al, 2017 ; Rayees et al, 2020 ). Studies have shown that TLR4-mediated inflammatory response plays an important role in heart, lung, liver, and cerebral I/R injury ( Rayees et al, 2020 ). After cerebral ischemia, TLR4 recognizes the endogenous substances released from brain tissue such as heat shock protein, fibrinogen, hyaluronic acid, heparan sulfate, etc., and finally activates NF-κB.…”

Section: Discussionmentioning

confidence: 99%

ATP2B1-AS1 Promotes Cerebral Ischemia/Reperfusion Injury Through Regulating the miR-330-5p/TLR4-MyD88-NF-κB Signaling Pathway

Wang

Tan

Zhu

et al. 2021

Front. Cell Dev. Biol.

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We aim to explore the expression and function of long non-coding RNA (lncRNA) ATP2B1-AS1 in a cerebral ischemia/reperfusion (I/R) injury. In this study, we established a middle cerebral artery occlusion/reperfusion (MCAO/IR) rat model and an OGD/R PC12 cell model to evaluate the expression and role of ATP2B1-AS1 in the cerebral I/R injury. We found that the expression of ATP2B1-AS1 was upregulated in both in vitro and in vivo cerebral I/R injury models. Knockdown of ATP2B1-AS1 increased the cell viability, inhibited apoptosis, and decreased the expressions of inflammation cytokines. The target of ATP2B1-AS1 was predicted and validated to be miR-330-5p. MiR-330-5p abrogated the regulatory effect of ATP2B1-AS1 on cell viability, apoptosis, and cytokines of OGD/R PC12 cells. Furthermore, the results showed that miR-330-5p targeted TLR4, which was also upregulated in the infarcted area of MCAO/IR rats and OGD/R PC12 cells. Overexpression of ATP2B1-AS1 increased the expressions of TLR4, MyD88, and NF-κB p65 of OGD/R PC12 cells, while the effect of ATP2B1-AS1 was abrogated by miR-330-5p. In addition, knockdown of ATP2B1-AS1 decreased the latency time, increased the time of passing the platform position, reduced the cerebral infarct volume, decreased neurological deficit scores, and reduced the number of damaged neurons of MCAO/IR rats that were subjected to the Morris water maze test. Taken together, our study indicates that ATP2B1-AS1 may be an attractive therapeutic target for the treatment of cerebral ischemic injuries.

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Macrophage TLR4 and PAR2 Signaling: Role in Regulating Vascular Inflammatory Injury and Repair

Cited by 44 publications

References 184 publications

Recombinant Antigen of Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2) Promotes M1 Repolarization of Porcine Alveolar Macrophages and Th1 Type Response

Recombinant Antigen of Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2) Promotes M1 Repolarization of Porcine Alveolar Macrophages and Th1 Type Response

Dihydronicotinamide Riboside Is a Potent NAD+ Precursor Promoting a Pro-Inflammatory Phenotype in Macrophages

ATP2B1-AS1 Promotes Cerebral Ischemia/Reperfusion Injury Through Regulating the miR-330-5p/TLR4-MyD88-NF-κB Signaling Pathway

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