Immunomodulatory matrix-bound nanovesicles mitigate acute and chronic pristane-induced rheumatoid arthritis

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.

Mitigation of influenza-mediated inflammation by immunomodulatory matrix-bound nanovesicles

“…Consistent with down-regulation of IFN-γ–related signaling, MBV limited the expression of iNOS in CD11b-expressing myeloid dendritic cells in the lung tissue in the present study. MBV have been shown to have a similar effect on iNOS-expressing, M1-like cells in vitro and in vivo in a model of rheumatoid arthritis ( 19 , 21 , 23 ). While these results have been consistently observed after in vitro and in vivo MBV treatment, the specific mechanisms of action remain unknown, and the identification of such mechanisms should be the subject of future studies.…”

“…These nanovesicles, identified as matrix-bound nanovesicles (MBVs), are a distinct subclass of extracellular vesicle (EV) that are different from fluid-phase exosomes and are enriched in anti-inflammatory and immunoregulatory-associated microRNA, proteins, and lipids (18)(19)(20). Previous studies of administered MBV show their ability to down-regulate proinflammatory immune responses and improve outcomes in animal models of acute ocular injury, rheumatoid arthritis, and chronic heart transplant rejection (23)(24)(25). In addition, MBVs have been shown to have minimal systemic and immune toxicity in vivo and biodistribution to immune tissues such as the spleen through various routes of administration (26).…”

Drug in Therapeutic Polymer: Sinomenine-Loaded Oxidation-Responsive Polymeric Nanoparticles for Rheumatoid Arthritis Treatment

“…39 Moreover, compared to HA, the increasing molecular weight of P-HA and PA-HA characterized by gel permeation chromatography (GPC) also suggested that PEG and Ald were sequentially linked to the HA backbone (Figure 1B), and the percentage of Ald modification could be deduced to be about 3.45% accordingly. To modulate the hydrophobicity and antioxidant capacity of the PAM-HA polymeric carrier, PA-HA was further modified with various ratios of Met, and the successful coupling of Met was confirmed by 1 H NMR (the characteristic peak −CH 3 was labeled in the figure) and elemental analysis (EA; Figure 1A and Table S1). The actual grafting rate of Met onto PA-HA can be extrapolated based on the amount of elemental sulfur by EA (as shown in Table 1).…”

Auriculotherapy Modulates Macrophage Polarization to Reduce Inflammatory Response in a Rat Model of Acne

“…The location of immune cells dispersed in the spleen, and their ability to migrate out of the spleen gives the spleen an important role in the immune system [ 21 ]. Regarding the choice of markers for splenic macrophages, this work refers to the studies of Crum et al and Rubio-Navarro et al [ 22 , 23 ] using CD68 + to label total macrophages in the spleen, CD68 + CD86 + CD163 − to denote M1-type macrophages, and CD68 + CD86 − CD163 + to denote M2-type macrophages.…”