PMID- 26109638 OWN - NLM STAT- MEDLINE DCOM- 20151026 LR - 20181113 IS - 1550-6606 (Electronic) IS - 0022-1767 (Print) IS - 0022-1767 (Linking) VI - 195 IP - 3 DP - 2015 Aug 1 TI - TGF-beta-Dependent Dendritic Cell Chemokinesis in Murine Models of Airway Disease. PG - 1182-90 LID - 10.4049/jimmunol.1500348 [doi] AB - Small airway chronic inflammation is a major pathologic feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Dendritic cells (DCs) accumulate around small airways in COPD. DCs are critical mediators of Ag surveillance and Ag presentation and amplify adaptive immune responses. How DCs accumulate around airways remains largely unknown. We use 2-photon DC imaging of living murine lung sections to directly visualize the dynamic movement of living DCs around airways in response to either soluble mediators (IL-1beta) or environmental stimuli (cigarette smoke or TLR3 ligands) implicated in COPD pathogenesis. We find that DCs accumulate around murine airways primarily by increasing velocity (chemokinesis) rather than directional migration (chemotaxis) in response to all three stimuli. DC accumulation maximally occurs in a specific zone located 26-50 mum from small airways, which overlaps with zones of maximal DC velocity. Our data suggest that increased accumulation of DCs around airways results from increased numbers of highly chemokinetic DCs entering the lung from the circulation with balanced rates of immigration and emigration. Increases in DC accumulation and chemokinesis are partially dependent on ccr6, a crucial DC chemokine receptor, and fibroblast expression of the integrin alphavbeta8, a critical activator of TGF-beta. alphavbeta8-Mediated TGF-beta activation is known to enhance IL-1beta-dependent fibroblast expression of the only known endogenous ccr6 chemokine ligand, ccl20. Taken together, these data suggest a mechanism by which alphavbeta8, ccl20, and ccr6 interact to lead to DC accumulation around airways in response to COPD-relevant stimuli. CI - Copyright (c) 2015 by The American Association of Immunologists, Inc. FAU - Hashimoto, Mitsuo AU - Hashimoto M AD - Department of Pathology, University of California, San Francisco, San Francisco, CA 94110; FAU - Yanagisawa, Haruhiko AU - Yanagisawa H AD - Department of Pathology, University of California, San Francisco, San Francisco, CA 94110; FAU - Minagawa, Shunsuke AU - Minagawa S AD - Department of Pathology, University of California, San Francisco, San Francisco, CA 94110; FAU - Sen, Debasish AU - Sen D AD - Department of Pathology, University of California, San Francisco, San Francisco, CA 94110; FAU - Ma, Royce AU - Ma R AD - Department of Pathology, University of California, San Francisco, San Francisco, CA 94110; FAU - Murray, Lynne A AU - Murray LA AD - Respiratory, Inflammation, and Autoimmunity, MedImmune, Gaithersburg, MD 20878 and Cambridge CB21 6GH, United Kingdom; FAU - Tsui, Ping AU - Tsui P AD - Respiratory, Inflammation, and Autoimmunity, MedImmune, Gaithersburg, MD 20878 and Cambridge CB21 6GH, United Kingdom; FAU - Lou, Jianlong AU - Lou J AD - Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110; and. FAU - Marks, James D AU - Marks JD AD - Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110; and. FAU - Baron, Jody L AU - Baron JL AD - Department of Medicine, University of California, San Francisco, San Francisco, CA 94110. FAU - Krummel, Matthew F AU - Krummel MF AD - Department of Pathology, University of California, San Francisco, San Francisco, CA 94110; FAU - Nishimura, Stephen L AU - Nishimura SL AD - Department of Pathology, University of California, San Francisco, San Francisco, CA 94110; stephen.nishimura@ucsf.edu. LA - eng GR - HL063993/HL/NHLBI NIH HHS/United States GR - P30DK026743/DK/NIDDK NIH HHS/United States GR - HL113032/HL/NHLBI NIH HHS/United States GR - P30 DK026743/DK/NIDDK NIH HHS/United States GR - P01 NS044155/NS/NINDS NIH HHS/United States GR - R01 HL113032/HL/NHLBI NIH HHS/United States GR - R01 HL063993/HL/NHLBI NIH HHS/United States GR - NS044155/NS/NINDS NIH HHS/United States GR - HL090662/HL/NHLBI NIH HHS/United States GR - R01 HL090662/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150624 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (CCL20 protein, mouse) RN - 0 (CCR6 protein, mouse) RN - 0 (Chemokine CCL20) RN - 0 (IL1B protein, mouse) RN - 0 (Integrins) RN - 0 (Interleukin-1beta) RN - 0 (Receptors, CCR6) RN - 0 (Smoke) RN - 0 (TLR3 protein, mouse) RN - 0 (Toll-Like Receptor 3) RN - 0 (Transforming Growth Factor beta) RN - 0 (integrin alphavbeta8) RN - O84C90HH2L (Poly I-C) SB - IM MH - Adaptive Immunity/immunology MH - Animals MH - Cell Movement/immunology MH - Chemokine CCL20/biosynthesis/immunology MH - Dendritic Cells/*immunology MH - Disease Models, Animal MH - Enzyme Activation/immunology MH - Fibroblasts/immunology MH - Integrins/biosynthesis/*immunology MH - Interleukin-1beta/biosynthesis/*immunology MH - Lung/diagnostic imaging MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Poly I-C/pharmacology MH - Pulmonary Disease, Chronic Obstructive/*immunology/pathology MH - Radiography MH - Receptors, CCR6/genetics/immunology MH - Smoke/adverse effects MH - Toll-Like Receptor 3 MH - Transforming Growth Factor beta/*immunology/metabolism PMC - PMC4506848 MID - NIHMS696220 EDAT- 2015/06/26 06:00 MHDA- 2015/10/27 06:00 PMCR- 2016/08/01 CRDT- 2015/06/26 06:00 PHST- 2014/02/11 00:00 [received] PHST- 2015/05/23 00:00 [accepted] PHST- 2015/06/26 06:00 [entrez] PHST- 2015/06/26 06:00 [pubmed] PHST- 2015/10/27 06:00 [medline] PHST- 2016/08/01 00:00 [pmc-release] AID - jimmunol.1500348 [pii] AID - 10.4049/jimmunol.1500348 [doi] PST - ppublish SO - J Immunol. 2015 Aug 1;195(3):1182-90. doi: 10.4049/jimmunol.1500348. Epub 2015 Jun 24.