Microglia and Interleukin-1β in Ischemic Retinopathy Elicit Microvascular Degeneration Through Neuronal Semaphorin-3A

Abstract

Objective-Proinflammatory cytokines contribute to the development of retinal vasculopathies. However, the role of these factors and the mechanisms by which they elicit their effects in retina are not known. We investigated whether activated microglia during early stages of ischemic retinopathy produces excessive interleukin-1β (IL-1β), which elicits retinal microvascular degeneration not directly but rather by triggering the release of the proapoptotic/repulsive factor semaphorin-3A (Sema3A)

Novel Noncompetitive IL-1 Receptor–Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth

“…1E). These observations support the concept that activated leukocytes responding to an inflammatory locus (uteroplacental unit in this case) are a significant source of IL-1, which in turn amplifies the inflammatory response (25,33); accordingly, the systemically administered large molecule Kineret (17.5 kDa) is effective on blood leukocytes, but contrary to 101.10 seems to have limited access to intrauterine/placental IL-1R wherein inflammation is triggered (by IL-1), consistent with documentation on IL-1 (∼17.5 kDa) (34, 35).…”

“…We previously showed that actions of 101.10 required presence of the ubiquitous IL-1RI (25). Accordingly, in this study again 101.10-FITC colocalized by immunohistochemistry with IL-1RI on the myometrial cell line hTERT-C3 and the macrophage cell line RAW-Blue mouse macrophages (Supplemental Fig.…”

“…The abdominal muscle layer was sutured, and the skin was closed with clips. A total of 100 mL 101.10 (1 mg/Kg/12 h), Kineret (4 mg/Kg/12 h), SR-11302 (1 mg/Kg/12 h), Y27632 (0.5 mg/Kg/12 h), or vehicle was injected s.c. in the neck 30 min before stimulation with IL-1b, LPS, or LTA (to allow distribution of drugs to target tissues, in line with a first efficacy preclinical study); all doses used were based on reported efficacy (17,24,25,28,29). Mice delivery was assessed every hour until term (G19-G19.5).…”

“…The host laboratory recently developed a small stable (all-d peptide) biased ligand modulator of IL-1R, specifically rytvela (labeled 101.10), which selectively binds to IL-1R and displays noncompetitive properties and functional selectivity toward specific pathways (24). The peptide rytvela has also been shown to be effective in numerous models of inflammation-linked diseases, including inflammatory bowel disease, contact dermatitis, hypoxicischemic newborn brain injuries, and ischemic retinopathies (24,25). We hereby propose a hitherto unexplored strategy of delaying infection-and inflammation-induced PTB using 101.10, which selectively inhibits IL-1R downstream stress-associated protein kinase (SAPK)/c-jun and Rho/Rho GTPase/Rho-associated coiledcoil-containing protein kinase (ROCK) pathways without significantly affecting NF-kB activation.…”

Molecular Signaling and Ocular Inflammation: An Update on the NOD-Like Receptors (NLRs)

“…Moreover, the context in which NLRP3 may participate in uveitis is more complicated beyond what is modeled by direct activation of TLR4. NLRP3 has been reported to be involved in other types of eye diseases such as ischemic retinopathy [34] and agerelated macular degeneration [35], an ocular disease whose association with inflammatory processes is increasingly being elucidated. Thus, it seems entirely likely that NLRP3 participates in other aspects of uveitis, especially since this pathway is known to play a role in shaping pathogenic Th17 effector responses.…”