Editorial: Sticking it to fibrocytes with serum amyloid P.

Fibrocytes are a bone marrow-derived mesenchymal population whose existence was first proposed over 150 years ago following the detailed microscopic observations of James Paget [1]. Whereas bloodborne connective tissue cell precursors are also described in the writings of Cohnheim, Metchnikov, Fischer, and Maximow [1], it was not until 1994 that the term “fibrocyte” was coined to describe this unique population of cells possessing the tissue-remodeling properties of fibroblasts and the proinflammatory properties of monocytes [2, 3]. Accumulating data gleaned from animal modeling and human studies suggest that circulating and/or local fibrocytes contribute to a broad range of chronic inflammatory conditions, including those affecting the lung, liver, autoimmune disease, skin, and even normal aging [3]. Fibrocyte differentiation is suppressed by serum amyloid P (SAP) [4], a short pentraxin protein that is produced by the liver as an acute-phase reactant. Interestingly, whereas the in vivo activitiy of SAP on human fibrocyte biology appears to involve certain Fc gamma receptors (Fc Rs) and aggregated IgG [5], the precise mechanism of the inhibitory effects of SAP on the monocyte-to-fibrocyte transition remains unclear. Fc Rs are cell surface molecules that bind or “stick” to the Fc portion of IgG to activate downstream signaling pathways that engender or impede critical events, such as phagocytosis, cell activation, release of soluble mediators, and microbe killing [6]. Human Fc Rs include Fc RI (CD64), Fc RIIa (CD32a), Fc RIIb (CD32b), Fc RIIIa (CD16a), and Fc RIIIb (CD16b). Murine studies have identified four classes of Fc Rs bearing similarity to those found in humans: Fc RI, Fc RII, Fc RIII (which seems most closely related to Fc IIa in humans), and Fc IV (which corresponds most closely to human Fc RIII) [7]. Despite differences in overall Fc fragment affinity and downstream signaling, murine studies of Fc Rs are considered helpful in terms of understanding human biology [8], and complementary mouse and human studies, such as those performed in the Crawford paper [9], can be particularly useful. Fc Rs differ in their binding affinity for the Fc portion of IgG. In mice and humans, Fc RI displays high affinity Fc fragment binding, whereas the affinity of the other Fc Rs is much lower. Fc RI, along with most other Fc Rs, contains an and -chains and functions as an activating receptor via ITAMs. In contrast, Fc RIIB contains only a single -chain containing a cytoplasmic ITIM [6]. Whereas it has long been known that Fc Rs, at least partially, mediate SAP’s inhibition of fibrocyte differentiation [5], a clear understanding of how the activating and inhibitory components synergize in this process is lacking—lacking, that is, until now. In this month’s issue of JLB, Crawford and colleagues [9] define, for the first time, the concerted roles of Fc Rs in mediating the inhibitory effects of SAP on fibrocyte development. The most salient features of this paper are as follows. With the use of a sophisticated translational approach combining sitedirected mutagenesis and murine modeling with studies of primary human cells, the authors demonstrate that in mice, the activity of SAP appears to be dependent on the common -chain of activating Fc Rs and specifically, on Fc RI (Table 1). Deletion of other activating receptors, such as Fc RIII, had no effect. As expected, deletion of Fc RIIb (the inhibitory Fc R) increased sensitivity to SAP; however, this effect was absent in the setting of triple deletion of Fc RIIb, III, and IV. Similar findings were seen in small interfering RNA-treated primary human cells, where knockdown of Fc common chain or Fc RI reduced sensitivity to SAP, but knockdown of other activating receptors, such as Fc RIIa (the human homologue of mouse Fc RIII) and Fc RIII (the human homolog of mouse Fc RIV), had no effect. Similar to the effects in mice, knockdown of Fc IIb increased SAP sensitivity. Interestingly, in the mouse and human studies, common chain and Fc RI deletion attenuated but did not completely abolish SAP sensitivity, suggesting that some of the effects of SAP require neither Fc RI nor an intact common -chain. These findings demonstrate that the inhibitory ef-