HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Published online before print August 3, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: jlb.0307195v1 82/5/1257    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Anand, R. J. Articles by Hackam, D. J. Search for Related Content PubMed PubMed Citation Articles by Anand, R. J. Articles by Hackam, D. J.

(Journal of Leukocyte Biology. 2007;82:1257-1265.)
© 2007 by Society for Leukocyte Biology

Hypoxia causes an increase in phagocytosis by macrophages in a HIF-1-dependent manner

Division of Pediatric Surgery, Children’s Hospital of Pittsburgh, and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

¹ Correspondence: Children’s Hospital of Pittsburgh, Department of Surgery, 3705 Fifth Avenue, 4A485 DeSoto, Pittsburgh, PA 15213, USA. E-mail: david.hackam{at}chp.edu

Phagocytosis is the process by which microbial pathogens are engulfed by macrophages and neutrophils and represents the first line of defense against bacterial infection. The importance of phagocytosis for bacterial clearance is of particular relevance to systemic inflammatory diseases, which are associated with the development of hypoxia, yet the precise effects of hypoxia on phagocytosis remain largely unexplored. We now hypothesize that hypoxia inhibits phagocytosis in macrophages and sought to determine the mechanisms involved. Despite our initial prediction, hypoxia significantly increased the phagocytosis rate of particles in vitro by RAW264.7 and primary peritoneal macrophages and increased phagocytosis of labeled bacteria in vivo by hypoxic mice compared with normoxic controls. In understanding the mechanisms involved, hypoxia caused no changes in RhoA-GTPase signaling but increased the phosphorylation of p38-MAPK significantly. Inhibition of p38 reversed the effects of hypoxia on phagocytosis, suggesting a role for p38 in the hypoxic regulation of phagocytosis. Hypoxia also significantly increased the expression of hypoxia-inducible factor-1 (HIF-1) in macrophages, which was reversed after p38 inhibition, suggesting a link between p38 activation and HIF-1 expression. It is striking that small interfering RNA knockdown of HIF-1 reversed the effects of hypoxia on phagocytosis, and overexpression of HIF-1 caused a surprising increase in phagocytosis compared with nontransfected controls, demonstrating a specific role for HIF-1 in the regulation of phagocytosis. These data indicate that hypoxia enhances phagocytosis in macrophages in a HIF-1-dependent manner and shed light on an important role for HIF-1 in host defense.

Key Words: critical illness • necrotizing enterocolitis • hypoxic stress • bacterial clearance • p38 • bacterial translocation

This article has been cited by other articles:

				A. R. Elia, P. Cappello, M. Puppo, T. Fraone, C. Vanni, A. Eva, T. Musso, F. Novelli, L. Varesio, and M. Giovarelli Human dendritic cells differentiated in hypoxia down-modulate antigen uptake and change their chemokine expression profile J. Leukoc. Biol., December 1, 2008; 84(6): 1472 - 1482. [Abstract] [Full Text] [PDF]