Monocytic Cell Gene Regulation by the Hypoxic Synovial Environment in Juvenile Idiopathic Arthritis: Implications for Disease Pathogenesis

Review Article

Maria Carla Bosco and Luigi Varesio
Affiliation: Laboratory of Molecular Biology, G Gaslini Institute, Genova, Italy


ABSTRACT

Persistent synovial inflammation, extensive blood vessel neoformation, and uncontrolled fibroblast proliferation are hallmarks of juvenile idiopathic arthritis (JIA). Dysregulated angiogenesis leads to a dysfunctional vascular network, decreasing blood flow and impairing tissue oxygenation. Oxygen supply is further reduced by the formation of a hyperplastic inflammatory mass, which increases diffusion distances from blood vessels to cells, resulting in areas of hypoperfusion and hypoxia. Monocytic cells are an important component of the leukocyte infiltrate in the joints of patients affected by JIA, where they accumulate within the hypoxic synovial microenvironment, and recent advances have shed light on their role in JIA pathogenesis. The present article provides an overview of the phenotypic and functional changes triggered by hypoxia in monocytic cells both in vitro and in vivo within the JIA synovium. The discussion revolves around studies of gene expression profiles, which give a good representation of the exquisite sensitivity and the complexity of monocytic cell response to oxygen levels similar to those present in the JIA inflamed synovium. Experimental evidence demonstrating the strict regulatory control exerted by hypoxia on monocytic cell recruitment/retention and functional properties at pathological sites is summarized. Furthermore, we outline the existing literature on the transcription pathways underlying hypoxia‐regulated gene expression. Finally, we address the possible link between hypoxia signaling and activation of the proangiogenic and inflammatory phenotype of monocytic cells infiltrating the synovial microenvironment, and discuss the implications of these findings for the persistence of chronic inflammation associated with JIA and for the development of new therapeutic strategies.

Keywords: juvenile idiopathic arthritis, monocytes/macrophages, hypoxia, angiogenic factors, chemokines, gene regulation, inflammation
Correspondence: Maria Carla Bosco, Laboratorio di Biologia Molecolare, Istituto Giannina Gaslini, Padiglione 2, Lgo Gerolamo Gaslini 5, 16147 Genova Quarto, Italy. Tel: (39)‐010‐5636633; Fax: (39)‐010‐3733346; e‐mail: mariacarlabosco@ospedale‐gaslini.ge.it