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Inhibitory ITAM Signaling by FcRI-FcR Chain Controls Multiple Activating Responses and Prevents Renal Inflammation¹

Yutaka Kanamaru^*,, Séverine Pfirsch^*,, Meryem Aloulou^*,, François Vrtovsnik^*,,, Marie Essig^*,,, Chantal Loirat^*,,, Georges Deschênes, Claudine Guérin-Marchand^*,, Ulrich Blank^2,3,*, and Renato C. Monteiro^2,3,*,

^* 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 (FcRI or CD89) by anti-FcRI Fab triggers potent inhibitory ITAM (ITAM_i) signaling through the associated FcR chain (FcRI-FcR ITAM_i) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcRI-FcR ITAM_i 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 ITAM_i 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 ITAM_i 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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; ITAM_i, inhibitory ITAM; PEG, polyethylene glycol; siRNA, small interfering RNA; UUO, unilateral ureteral obstruction.

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The JI 2008 180: 2005-2006. [Full Text]