title: Rac1 signaling regulates neutrophil-dependent tissue damage in experimental colitis.
abstract: Excessive neutrophil recruitment in the colon is a major feature in acute colitis although the signaling mechanisms behind colonic recruitment of neutrophils remain elusive. Herein, we hypothesized that Rac1 activity might play an important role in neutrophil infiltration in the inflamed colon. Female Balb/c mice were treated with the Rac1 inhibitor NSC23766 (0.5 and 5mg/kg) before and daily after administration of 5% dextran sodium sulfate (DSS). Colonic tissue was collected for quantification of neutrophil recruitment, interleukin-6 (IL-6) and CXC chemokine formation as well as histological damage score five days after challenge with DSS. Rac1 activity was determined by western blot and Mac-1 expression by flow cytometry in neutrophils. Administration of NSC23766 decreased DSS-induced neutrophil recruitment and tissue damage in the colon. Rac1 inhibition decreased colonic formation of IL-6 and CXC chemokines in experimental colitis. Chemokine challenge increased Rac1 activity in neutrophils and NSC23766 markedly reduced this neutrophil activity of Rac1. Inhibition of Rac1 abolished CXC chemokine-induced neutrophil chemotaxis and up-regulation of Mac-1 in vitro. Taken together, Rac1 signaling plays a significant role in controlling accumulation of neutrophils and tissue injury in experimental colitis. Thus, our novel results suggest that targeting Rac1 signaling might be a useful way to protect against neutrophil-mediated tissue injury in acute colitis.
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden; Department of Gastroenterology, Zhujiang Hospital of Southern Medical University, 510282 Guangzhou, China.
authors.forename: Changhui
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden.
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden.
authors.forename: Rundk
authors.initials: R
authors.lastname: Hwaiz
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden. Electronic address: henrik.thorlacius@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D003092:Colitis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D000634:Aminoquinolines; C487513:NSC 23766; D009479:Neuropeptides; D011743:Pyrimidines; C484602:Rac1 protein, mouse; D020830:rac1 GTP-Binding Protein
keywords: Adhesion; Inflammation; Leukocytes; Migration; Neutrophils