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RI-FcR
Chain Controls Multiple Activating Responses and Prevents Renal Inflammation1
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* Institut National de la Santé et de la Recherche Médicale, Unité 699,
Université Paris 7-Denis Diderot, Faculté de Médecine, Site Xavier Bichat,
Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Néphrologie, and
Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Service de Néphrologie Pédiatrique, Paris, France
Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (Fc
RI or CD89) by anti-FcRI Fab triggers potent inhibitory ITAM (ITAMi) signaling through the associated FcR
chain (FcRI-FcR ITAMi) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcRI-FcR ITAMi signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcRI-Fc ITAMi signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcRI-FcR ITAMi signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.
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1 This work was supported by Grants Emergence05, Mime06, Physio06 from l’Agence Nationale pour la Recherche and from Association pour l’Utilisation du Rein Artificiel. Y.K. was a recipient of fellowships from Institut National de la Santé et de la Recherche Médicale and Fondation pour la Recherche Médicale.
2 U.B. and R.C.M. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Renato C. Monteiro and Dr. Ulrich Blank, Institut National de la Santé et de la Recherche Médicale, Unité 699, Immunopathologie Rénale, Récepteurs et Inflammation, Faculté de Medicine, Paris 7, Site Xavier Bichat, 16 rue Henri Huchard, BP416 75870 Paris, France. E-mail addresses: monteiro{at}bichat.inserm.fr and ublank{at}bichat.inserm.fr
4 Abbreviations used in this paper: ESRD, end-stage renal disease; GBM, glomerular basal membrane; SHP, Src homology protein; TREM, triggering receptor expressed on myeloid cell; ITAMi, inhibitory ITAM; PEG, polyethylene glycol; siRNA, small interfering RNA; UUO, unilateral ureteral obstruction.
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