Fcγ receptor–dependent expansion of a hyperactive monocyte subset in lupus‐prone mice

Abstract

Objective. Lupus-prone BXSB mice develop monocytosis characterized by selective accumulation of the Gr-1-monocyte subset. The aim of this study was to explore the possible role of activating IgG Fc receptors (Fc␥R) in the development of monocytosis and to characterize the functional phenotype of the Gr-1-subset that accumulates in lupus-prone mice bearing the NZBtype defective Fcgr2b allele for the inhibitory Fc␥RIIB.Methods. The development of monocytosis was analyzed in BXSB and anti-IgG2a rheumatoid factortransgenic C57BL/6 mice deficient in activating Fc␥R. Moreover, we assessed the expression levels of activating Fc␥R and inhibitory Fc␥RIIB on Gr-1؉ and Gr-1-monocyte subsets in C57BL/6 mice bearing the C57BL/ 6-type or the NZB-type Fcgr2b allele.Results. We observed monocytosis with expansion of the Gr-1-subset in anti-IgG2a-transgenic C57BL/6 mice expressing IgG2a, but not in those lacking IgG2a. Moreover, monocytosis barely developed in BXSB and anti-IgG2a-transgenic C57BL/6 mice deficient in activating Fc␥R. The Gr-1-subset that accumulated in lupus-prone mice displayed a unique hyperactive phenotype. It expressed very low levels of inhibitory Fc␥RIIB, due to the presence of the NZB-type Fcgr2b allele, but high levels of activating Fc␥RIV. This was in contrast to high levels of Fc␥RIIB expression and no Fc␥RIV expression on the Gr-1؉ subset. Conclusion. Our results demonstrated a critical role of activating Fc␥R in the development of monocytosis and in the expansion of a Gr-1-Fc␥RIIB lowFc␥RIV؉ hyperactive monocyte subset in lupus-prone mice. Our findings further highlight the importance of the NZB-type Fcgr2b susceptibility allele in murine lupus, the presence of which induces increased production of hyperactive monocytes as well as dysregulated activation of autoreactive B cells.

Monocyte Subsets Responsible for Immunoglobulin G-Dependent Effector Functions In Vivo

“…Taken together, our experiments demonstrate that despite widespread expression of FcgRs on innate immune effector cells, a rather select subpopulation of monocytes may be crucial for antibody-mediated platelet phagocytosis and B cell depletion in mice in vivo. In the light of the recent finding that an FcgRIV-positive monocyte subset is selectively expanded in lupus-prone mice, it seems possible that this cell type is centrally involved in mediating IgG-dependent tissue pathology (Santiago-Raber et al, 2009. Despite functional overlaps between mouse and human FcgRs and the respective mouse and human monocyte subsets, there are also important functional differences, necessitating further studies before definitive conclusions can be drawn for the human system (Gordon and Taylor, 2005;Ziegler-Heitbrock et al, 2010).…”

Monocyte homeostasis and the plasticity of inflammatory monocytes

“…Murine Ly6C lo monocytes also express a wide range of Fcc receptors and may mediate antibody dependent cellular cytotoxicity [78]. This is echoed in a model of lupus, where Ly6C lo monocytes are expanded and contribute to pathology in an FccR-dependent manner [79].…”

Molecular and Cellular Pathways of Immunoglobulin G Activity In Vivo

“…As most of the animal studies have been performed with passive models of ITP, further studies will be necessary to elucidate the contribution of other cells of the mononuclear phagocyte system under clinically more relevant chronic forms of the disease. A role for resident monocytes under chronic inflammatory conditions has been suggested by studies showing that this monocyte subset is expanded and hyperactive in SLE-prone BXSB mice and in human patients having complications after heart surgery [70][71][72].…”