Pharmacological inhibition of receptor-interacting protein kinase 2 (RIPK2) elicits neuroprotective effects following experimental ischemic stroke

Larochelle, Jonathan; Howell, John Aaron; Yang, Changjun; Liu, Lei; Gunraj, Rachel E.; Stansbury, Sofia M.; de Oliveira, Antonio Carlos Pinheiro; Baksh, Shairaz; Candelario-Jalil, Eduardo

doi:10.1016/j.expneurol.2024.114812

Cited by 3 publications

References 58 publications

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RIPK2 is crucial for the microglial inflammatory response to bacterial muramyl dipeptide but not to lipopolysaccharide

Yang,

Machado da Silva,

Howell

et al. 2024

Preprint

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Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is a kinase that plays an essential role in the modulation of innate and adaptive immune responses. As a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs), it is implicated in the signaling triggered by recognition of microbe-associated molecular patterns by NOD1/2 and TLRs. Upon activation of these innate immune receptors, RIPK2 mediates the release of pro-inflammatory factors by activating mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). However, whether RIPK2 is essential for downstream inflammatory signaling following the activation of NOD1/2, TLRs, or both remains controversial. In this study, we examined the role of RIPK2 in NOD2- and TLR4-dependent signaling cascades following stimulation of microglial cells with bacterial muramyl dipeptide (MDP), a NOD2 agonist, or lipopolysaccharide (LPS), a TLR4 agonist. We utilized a highly specific proteolysis targeting chimera (PROTAC) molecule, GSK3728857A, and found dramatic degradation of RIPK2 in a concentration- and time-dependent manner. Importantly, the PROTAC completely abolished MDP-induced increases in iNOS and COX-2 protein levels and pro-inflammatory gene transcription of Nos2, Ptgs2, Il-1β, Tnfα, Il6, Ccl2, and Mmp9. However, increases in iNOS and COX-2 proteins and pro-inflammatory gene transcription induced by the TLR4 agonist, LPS, were only slightly attenuated with the GSK3728857A pretreatment. Further findings revealed that the RIPK2 PROTAC completely blocked the phosphorylation and activation of p65 NF-κB and p38 MAPK induced by MDP, but it had no effects on the phosphorylation of these two mediators triggered by LPS. Collectively, our findings strongly suggest that RIPK2 plays an essential role in the inflammatory responses of microglia to bacterial MDP but not to LPS.

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RIPK2 is crucial for the microglial inflammatory response to bacterial muramyl dipeptide but not to lipopolysaccharide

Yang,

Machado da Silva,

Howell

et al. 2024

Preprint

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RIPK2 Is Crucial for the Microglial Inflammatory Response to Bacterial Muramyl Dipeptide but Not to Lipopolysaccharide

Yang,

da Silva,

Howell

et al. 2024

IJMS

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Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is a kinase that is essential in modulating innate and adaptive immune responses. As a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs), it is implicated in the signaling triggered by recognition of microbe-associated molecular patterns by NOD1/2 and TLRs. Upon activation of these innate immune receptors, RIPK2 mediates the release of pro-inflammatory factors by activating mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). However, whether RIPK2 is essential for downstream inflammatory signaling following the activation of NOD1/2, TLRs, or both remains controversial. In this study, we examined the role of RIPK2 in NOD2- and TLR4-dependent signaling cascades following stimulation of microglial cells with bacterial muramyl dipeptide (MDP), a NOD2 agonist, or lipopolysaccharide (LPS), a TLR4 agonist. We utilized a highly specific proteolysis targeting chimera (PROTAC) molecule, GSK3728857A, and found dramatic degradation of RIPK2 in a concentration- and time-dependent manner. Importantly, the PROTAC completely abolished MDP-induced increases in iNOS and COX-2 protein levels and pro-inflammatory gene transcription of Nos2, Ptgs2, Il-1β, Tnfα, Il6, Ccl2, and Mmp9. However, increases in iNOS and COX-2 proteins and pro-inflammatory gene transcription induced by the TLR4 agonist, LPS, were only slightly attenuated with the GSK3728857A pretreatment. Further findings revealed that the RIPK2 PROTAC completely blocked the phosphorylation and activation of p65 NF-κB and p38 MAPK induced by MDP, but it had no effects on the phosphorylation of these two mediators triggered by LPS. Collectively, our findings strongly suggest that RIPK2 plays an essential role in the inflammatory responses of microglia to bacterial MDP but not to LPS.

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Immune response in cerebral ischemic injury: interaction and therapeutic potential

Gao

2024

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Cerebral ischemia primarily results from vascular stenosis or blockage, which activates inflammatory cells and triggers an immune response. An excessive immune response can exacerbate the damage caused by cerebral ischemia. In this review, the keywords “immune response” and “cerebral ischemia” were entered into the PubMed database, yielding 241 articles, of which 141 were included in the analysis. Relevant literature from 2021 to 2024 was summarized, classified, and synthesized to delineate advancements in this field. Consequently, in exploring the basic physiology of immune responses and brain injury, we found that microglia can phagocytose dead neurons, thereby ameliorating ischemic brain injury. However, inflammatory cells accumulate and attack blood vessels and nerve cells following cerebral ischemia, resulting in additional damage. As a result, targeting CD8 T cells, astrocytes, superoxide dismutase (SOD), interleukin-10 (IL-10), tumor necrosis factor (TNF), NLRP3, and the NF-κB signaling pathway can help mitigate this damage. Furthermore, the specific mechanisms and efficacy of therapeutic drugs in recent years were analyzed, revealing their potential to repair the blood-brain barrier, endothelial cells, and neurons, while also reducing infarct size and inflammatory responses. Together, we highlight that immune cells, particularly microglia, present new therapeutic breakthroughs in neuron phagocytosis, improvement of inflammatory responses, and reduction of vascular endothelial damage. These findings provide clinicians and researchers with cutting-edge references for treatment strategies.

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Pharmacological inhibition of receptor-interacting protein kinase 2 (RIPK2) elicits neuroprotective effects following experimental ischemic stroke

Cited by 3 publications

References 58 publications

RIPK2 is crucial for the microglial inflammatory response to bacterial muramyl dipeptide but not to lipopolysaccharide

RIPK2 is crucial for the microglial inflammatory response to bacterial muramyl dipeptide but not to lipopolysaccharide

RIPK2 Is Crucial for the Microglial Inflammatory Response to Bacterial Muramyl Dipeptide but Not to Lipopolysaccharide

Immune response in cerebral ischemic injury: interaction and therapeutic potential

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