Artificial extracellular matrices composed of collagen I and high sulfated hyaluronan modulate monocyte to macrophage differentiation under conditions of sterile inflammation

Abstract

Integration of biomaterials into tissues is often disturbed by unopposed activation of macrophages. Immediately after implantation, monocytes are attracted from peripheral blood to the implantation site where they differentiate into macrophages. Inflammatory signals from the sterile tissue injury around the implanted biomaterial mediate the differentiation of monocytes into inflammatory M1 macrophages (M1) via autocrine and paracrine mechanisms. Suppression of sustained M1 differentiation is thought to be crucial to improve implant healing. Here, we explore whether artificial extracellular matrix (aECM) composed of collagen I and hyaluronan (HA) or sulfated HA-derivatives modulate this monocyte differentiation. We mimicked conditions of sterile tissue injury in vitro using a specific cytokine cocktail containing MCP-1, IL-6 and IFNγ, which induced in monocytes a phenotype similar to M1 macrophages (high expression of CD71, HLA-DR but no CD163 and release of high amounts of pro-inflammatory cytokines IL-1β, IL-6, IL-8, IL-12 and TNFα). In the presence of aECMs containing high sulfated HA this monocyte to M1 differentiation was disturbed. Specifically, pro-inflammatory functions were impaired as shown by reduced secretion of IL-1β, IL-8, IL-12 and TNFα. Instead, release of the immunregulatory cytokine IL-10 and expression of CD163, both markers specific for anti-inflammatory M2 macrophages (M2), were induced. We conclude that aECMs composed of collagen I and high sulfated HA possess immunomodulating capacities and skew monocyte to macrophage differentiation induced by pro-inflammatory signals of sterile injury toward M2 polarization suggesting them as an effective coating for biomaterials to improve their integration.

Solubilized extracellular matrix from brain and urinary bladder elicits distinct functional and phenotypic responses in macrophages

“…The detection kit utilized in this study cannot detect low molecular weight HA and it is possible that B-ECM did contain significant quantities of HA but at a lower molecular weight. This hypothesis could account for the inflammatory activity of B-ECM as low molecular weight HA has been shown to be inflammatory while high molecular weight has been shown to be anti-inflammatory [36,83,84]. Additional proteoglycans such as myelin, which is abundant in brain ECM, have also been shown to be inflammatory at low molecular weight [34,37].…”

Selective recruitment of non-classical monocytes promotes skeletal muscle repair

“…Monocytes and macrophages may also direct their own behavior and fate through paracrine and autocrine signaling. Monocytes and macrophages produce tumor necrosis factor-alpha (TNF-α) and IL-1β which leads to self-amplification of inflammatory responses [43], and their phagocytosis of cellular debris results in downregulation of inflammatory cytokine expression [44]. Thus, controlling the accumulation of specific monocyte and macrophage populations in vivo represents an important step in better understanding their role in the intricate wound healing process.…”

Anti-Inflammatory Strategies in Cartilage Repair

“…53 However, other reports suggested that chondroitin-4-sulfate inhibited the enhanced expression of COX-2 and prostaglandin E (PGE) synthases 1, but had no effect on the IL-1b-induced decrease of IkBa and nuclear translocation of NF-kB 54 ; the extent of sulfation influenced the responsiveness of inflammation. 55 Synthetically sulfated HA was at first characterized as an inhibitor of TNFa. 56 HA is an anionic nonsulfated GAG that acts as a crucial structural component of the ECM and as an important mediator of leukocyte adhesion and migration.…”