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

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).

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

Ischemic stroke induces a debilitating neurological insult, where inflammatory processes contribute greatly to the expansion and growth of the injury. Receptor-interacting protein kinase 2 (RIPK2) is most well-known for its role as the obligate kinase for NOD1/2 pattern recognition receptor signaling and is implicated in the pathology of various inflammatory conditions. Compared to a sham-operated control, ischemic stroke resulted in a dramatic increase in the active, phosphorylated form of RIPK2, indicating that RIPK2 may be implicated in the response to stroke injury.

Elastin-like polypeptide delivery of anti-inflammatory peptides to the brain following ischemic stroke.

Inflammatory processes are activated following ischemic stroke that lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation-induced secondary injury. Here, we report that SynB1-ELP-p50i, a novel protein inhibitor of the nuclear factor kappa B (NF-κB) inflammatory cascade bound to the drug carrier elastin-like polypeptide (ELP), decreases NF-κB induced inflammatory cytokine production in cultured macrophages, crosses the plasma membrane and accumulates in the cytoplasm of both neurons and microglia in vitro, and accumulates at the infarct site where the blood-brain barrier (BBB) is compromised following middle cerebral artery occlusion (MCAO) in rats. Additionally, SynB1-ELP-p50i treatment reduces infarct volume by 11.

Elastin-like polypeptide delivery of anti-inflammatory peptides to the brain following ischemic stroke.

Inflammatory processes are activated following ischemic strokes and lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation-induced secondary injury. Here, we report that SynB1-ELP-p50i, a novel protein inhibitor of the nuclear factor kappa B (NF-κB) inflammatory cascade bound to drug carrier elastin-like polypeptide (ELP), is able to enter both neurons and microglia, cross the blood-brain barrier, localize exclusively in the ischemic core and penumbra in Wistar-Kyoto and spontaneously hypertensive rats (SHRs), and reduce infarct volume in male SHRs. Additionally, in male SHRs, SynB1-ELP-p50i treatment improves survival for 14 days following stroke with no effects of toxicity or peripheral organ dysfunction.

Elastin-Like Polypeptide: VEGF-B Fusion Protein for Treatment of Preeclampsia.

[Figure: see text].

Targeting the NF-κB pathway for therapy of ischemic stroke.

Ischemic strokes occur when a major cerebral artery or its branches are occluded, resulting in activation of inflammatory processes that cause secondary tissue injury, breakdown of the blood-brain barrier, edema or hemorrhage. Treatments that inhibit inflammatory processes may thus be highly beneficial. A key regulator of the inflammatory process is the nuclear factor kappa B (NF-κB) pathway.

Biopolymer-Delivered, Maternally Sequestered NF-κB (Nuclear Factor-κB) Inhibitory Peptide for Treatment of Preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy that causes significant acute and long-term risk to the mother and the baby. The multifaceted maternal syndrome is driven by overproduction of circulating anti-angiogenic factors, widespread inflammation, and endothelial dysfunction. Nuclear factor-κB (NF-κB) is a transcription factor that plays a central role in the inflammatory response.