title: Anti-inflammatory effect of Natterins, the major toxins from the Thalassophryne nattereri fish venom is dependent on TLR4/MyD88/PI3K signaling pathway.
abstract: Here we evaluated whether Natterins affect the leukocyte-endothelial cell interaction, hampering leukocyte mobilization and extravasation. Leukocyte-endothelial cell interactions were evaluated in venules of mouse cremaster muscle using intravital microscopy. We reported that low doses of Natterins interfere with the cell capturing, inhibiting the interaction of blood neutrophils with the post-capillary venules induced by the TLR4 agonist LPS, or the chemokine KC. Using endotoxemic mice challenged with LPS, we confirmed that Natterins reduce neutrophil accumulation in the peritoneum exudates. The rolling of leukocytes induced by KC or LPS was not impaired in Natterins-treated TLR2, MyD88 deficient or TLR4 mutant mice, indicating that TLR2- or TLR4-MyD88-mediated signals are required for the anti-inflammatory effect of Natterins. The inhibitory effect was not influenced by endogenous regulators of inflammation such as IL-10, corticosteroids, the HO-1 or the antagonist of the receptor of IL-1, nor by the disruption of their proteolytic activity. However, it was completely dependent on the activation of serine/threonine phosphatases and the PI3K signaling pathway, but independent on increased proteasome activity. This work started asking how the main toxins in the T nattereri venom contributes for the deficient influx of inflammatory leukocytes, which consequently drive to the delayed inflammatory reaction finalization in injured tissue; and finished demonstrating that Natterins can control the leukocyte-endothelial wall interactions in a mechanism dependent on negative signals derived from TLR2-TLR4/Myd88 signaling cascade. Interestingly, we confirmed that the antagonist effect of Natterins is mediated by the activation of serine/threonine phosphatases and by the key signaling PI3K molecule.
authors.affiliation: Immunoregulation Unit, Special Laboratory of Applied Toxinology, Butantan Institute, Av. Vital Brazil, 1500, Butantan 05503-009, São Paulo, Brazil.
authors.forename: Marcio Jose
authors.initials: MJ
authors.lastname: Ferreira
authors.affiliation: Immunoregulation Unit, Special Laboratory of Applied Toxinology, Butantan Institute, Av. Vital Brazil, 1500, Butantan 05503-009, São Paulo, Brazil.
authors.forename: Carla
authors.initials: C
authors.lastname: Lima
authors.affiliation: Immunoregulation Unit, Special Laboratory of Applied Toxinology, Butantan Institute, Av. Vital Brazil, 1500, Butantan 05503-009, São Paulo, Brazil. Electronic address: mlferrei@usp.br.
authors.forename: Monica
authors.initials: M
authors.lastname: Lopes-Ferreira
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004727:Endothelium / Q000473:pathology; D005397:Fish Venoms / Q000737:chemistry / Q000494:pharmacology*; D005400:Fishes, Poisonous / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000235:genetics; D020556:Neutrophil Infiltration / Q000187:drug effects; D010538:Peritonitis / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012772:Shock, Septic / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005397:Fish Venoms; D053594:Myeloid Differentiation Factor 88; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse
keywords: Fish venom; Leukocyte rolling; Natterins; PI3K; Protein serine/threonine phosphatases; TLRs and MyD88 signaling