Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti-inflammatory immune cells, especially macrophages. Modulation of macrophage phenotype, specifically an M1 to M2, pro- to anti-inflammatory transition, can be induced by biologic scaffold materials composed of extracellular matrix (ECM). The ECM-based immunomodulatory effect is thought to be mediated in part through recently identified matrix-bound nanovesicles (MBV) embedded within ECM. Isolated MBV was delivered via intravenous (i.v.) or peri-articular (p.a.) injection to rats with pristane-induced arthritis (PIA). The results of MBV administration were compared to intraperitoneal (i.p.) administration of methotrexate (MTX), the clinical standard of care. Relative to the diseased animals, i.p. MTX, i.v. MBV, and p.a. MBV reduced arthritis scores in both acute and chronic pristane-induced arthritis, decreased synovial inflammation, decreased adverse joint remodeling, and reduced the ratio of synovial and splenic M1 to M2 macrophages (p < 0.05). Both p.a. and i.v. MBV reduced the serum concentration of RA and PIA biomarkers CXCL10 and MCP-3 in the acute and chronic phases of disease (p < 0.05). Flow-cytometry revealed the presence of a systemic CD43hi/His48lo/CD206+, immunoregulatory monocyte population unique to p.a. and i.v. MBV treatment associated with disease resolution. The results show that the therapeutic efficacy of MBV is equal to that of MTX for the management of acute and chronic pristane-induced arthritis and, further, this effect is associated with modulation of local synovial macrophages and systemic myeloid populations.
Highlights
The extracellular matrix (ECM) of all tissues and organs represents the secreted product of resident cells and consists of a complex mixture of structural and bio-active molecules; the ECM comprises an ideal microenvironment for cells in the healthy state[1,2]
The components of ECM that mediate an anti-inflammatory macrophage phenotype are not fully understood, but it has been shown that this macrophage phenotype transition can be induced by exposure to the degradation products of acellular biologic scaffold materials composed of mammalian ECM4–7,10– 13,16–19, including recently characterized, matrix-bound nanovesicles (MBV)[7,9,20]
In vitro studies have shown that MBV, independent of their parent ECM, are able to recapitulate the effects of whole ECM upon macrophage phenotype[7,20]
Summary
The extracellular matrix (ECM) of all tissues and organs represents the secreted product of resident cells and consists of a complex mixture of structural and bio-active molecules; the ECM comprises an ideal microenvironment for cells in the healthy state[1,2]. ECM derived from healthy tissues and configured into surgical mesh materials, topical powders, or hydrogels, has been shown to promote an anti-inflammatory, regulatory macrophage phenotype[4,5,6,7,8,9,10,11,12,13,14,15]. The components of ECM that mediate an anti-inflammatory macrophage phenotype are not fully understood, but it has been shown that this macrophage phenotype transition can be induced by exposure to the degradation products of acellular biologic scaffold materials composed of mammalian ECM4–7,10– 13,16–19, including recently characterized, matrix-bound nanovesicles (MBV)[7,9,20]. In vitro studies have shown that MBV, independent of their parent ECM, are able to recapitulate the effects of whole ECM upon macrophage phenotype[7,20]
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