The connection between Serum Amyloid P/Pentraxin-2 and IL-10 in the treatment of kidney fibrosis

In models of kidney fibrosis, systemic administration of Serum amyloid P or Pentraxin-2 (PTX-2) significantly inhibits fibrosis through a monocyte/macrophage-dependent mechanism, and as such represents a potential novel therapy for the treatment of chronic inflammation with fibrosis. In transgenic Coll-GFP reporter mice, PTX-2 inhibited myofibroblast synthesis of collagen, but myofibroblast numbers were unaffected. PTX-2 is deposited on injured tissue and debris in the kidney, and is detected in endosomes/phagosomes of macrophages (Mϕs). It does not bind to, or inhibit collagen production by, fibroblasts in vitro, but it binds with high affinity to activating Fcγ receptors on monocytes/ Mϕs. Purified Mϕs from fibrotic kidney are less activated and produce 20 fold more IL10 in mice treated with PTX-2. To test the direct role of IL10 in the inhibition of fibrosis mediated by PTX-2, we systemically administered IL10 producing adenovirus (Ad-IL10 and control virus (Ad-mock) in models of kidney fibrosis. Ad-IL10 resulted in high levels of systemic IL10 and markedly attenuated fibrosis accumulation in the kidney. Systemic IL10 inhibited both monocyte/ Mϕ activation and myofibroblast proliferation and activation in vivo. We propose that the major mechanism of action of PTX-2 is to switch M2 or wound healing Mϕs into regulatory Mϕs. Local generation of IL10 blocks Mϕs driven fibrosis and directly inhibits myofibroblasts.