Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis

Abstract

Microvesicles (MVs) are emerging as a new mechanism of intercellular communication by transferring cellular lipid and protein components to target cells, yet their function in disease is only now being explored. We found that neutrophil-derived MVs were increased in concentration in synovial fluid from rheumatoid arthritis patients compared to paired plasma. Synovial MVs overexpressed the proresolving, anti-inflammatory protein annexin A1 (AnxA1). Mice deficient in TMEM16F, a lipid scramblase required for microvesiculation, exhibited exacerbated cartilage damage when subjected to inflammatory arthritis. To determine the function of MVs in inflammatory arthritis, toward the possibility of MV-based therapeutics, we examined the role of immune cell–derived MVs in rodent models and in human primary chondrocytes. In vitro, exogenous neutrophil-derived AnxA1+ MVs activated anabolic gene expression in chondrocytes, leading to extracellular matrix accumulation and cartilage protection through the reduction in stress-adaptive homeostatic mediators interleukin-8 and prostaglandin E2. In vivo, intra-articular injection of AnxA1+ MV lessened cartilage degradation caused by inflammatory arthritis. Arthritic mice receiving adoptive transfer of whole neutrophils displayed abundant MVs within cartilage matrix and revealed that MVs, but not neutrophils themselves, can penetrate cartilage. Mechanistic studies support a model whereby MV-associated AnxA1 interacts with its receptor FPR2 (formyl peptide receptor 2)/ALX, increasing transforming growth factor–b production by chondrocytes, ultimately leading to cartilage protection. We envisage that MVs, either directly or loaded with therapeutics, can be harnessed as a unique therapeutic strategy for protection in diseases associated with cartilage degeneration.

Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles

“…Although MVs are able to potentiate inflammation by up-regulating the production of cytokines and chemokines and the expression of adhesion molecules as well as activating proinflammatory signaling pathways (49 -52), other studies demonstrate an anti-inflammatory effect (53). For example, MVs generated from human neutrophils decreased neutrophil recruitment and facilitated the resolution of inflammation, and they were also capable of entering cartilage and protecting joints during inflammatory arthritis, processes mediated by Annexin A1 (36,53). MVs also promoted the resolution of inflammation in vivo during sepsis (54).…”

“…MVs are known to exert both a pro-and anti-inflammatory effect during inflammation (35,36), the biological function of the MVs generated during activation was examined. Regardless of the parent cell, MVs generated during activation triggered a respiratory response in neutrophils and facilitated the production of oxidants (Fig.…”

Hydroalcoholic crude extract of Casearia sylvestris Sw. reduces chronic post-ischemic pain by activation of pro-resolving pathways

“…For muscle investigation, samples were processed for staining and analysis using methodolgy previously described (Norling et al, 2016;Headland et al, 2015). marginal pannus and invading the synovium).…”

Lipid bilayer nanoparticle-based drug delivery systems in the treatment of rheumatoid arthritis: a glance at liposomes and exosomes

“…(3) delivery, which have aroused extensive attention in the past two decades [18]. With similar vesicle size and lipid bilayer structure to liposomes, exosomes not only display the advantages of liposomes, but exhibit additional benefits due to their cellular origin, such as good biocompatibility, natural protein decoration and immunoregulatory activity, which may be valuable features for the rational design of exosome-based drug delivery systems for RA treatment [18][19][20][21]. As a young and developing field, exosomes have been employed for drug delivery in the treatment of inflammatory and other diseases, but their application as drug carriers for RA therapy is largely unexplored [22][23][24].…”