Targeted Reinforcement of Macrophage Reprogramming Toward M2 Polarization by IL-4-Loaded Hyaluronic Acid Particles

Abstract

Alteration of macrophage polarization from inflammatory (M1) to anti-inflammatory (M2) phenotype can have striking implications for the regeneration of injured tissues, treatment of inflammatory diseases, and relief of autoimmune disorders. Although certain cytokines like interleukin (IL)-4 and IL-13 are capable of inducing M2 macrophage polarization, their therapeutic potential in vivo is suffering from low efficacy due to their instability and poor access to target cells. Here, we report the synthesis of IL-4-loaded hyaluronic acid (HA) particle for the targeted delivery of cytokines through the high affinity of HA to CD44 receptors of macrophages. HA carriers composed of low, middle, and high molecular weight (MW) polymers were synthesized using divinyl sulfone (DVS) cross-linking. The MW of HA had a negligible effect on the physicochemical properties and biocompatibility of the macrophages, but as an indicative of M2 polarization, a significant change in the arginase-1 (Arg-1) activity, TNF-α release, and IL-10 secretion was observed for the HA particles prepared with high MW polymers. Therefore, these particles were loaded with IL-4 for simultaneous macrophage targeting and M1 to M2 reprogramming, evidenced by a remarkable increase in the Arg-1 to iNOS ratio, as well as CD163 and CD206 upregulation in the M1 macrophages, which were initially triggered by lipopolysaccharide and interferon-γ.

Hypoxia activates SUMO-1-HIF-1α signaling pathway to upregulate pro-inflammatory cytokines and permeability in human tonsil epithelial cells

“…IL-4 is a potent inducer for M2 macrophage polarization and differentiation (Supplementary Fig. 1), consistent with previous studies [27]. We found that a co-culture of IL-4-induced M2 macrophages and HTECs signi cantly attenuated hypoxia-induced upregulation of proin ammatory cytokines IL-6, IL-8, and TNF-α (Fig.…”

The Addition of High Doses of Hyaluronic Acid to a Biphasic Bone Substitute Decreases the Proinflammatory Tissue Response

“…Beyond this, it is conceivable that the decrease of the pro-inflammatory tissue response is an indicator for a preponderance of anti-inflammatory reactivity. This would mean that the addition of higher concentrations of HMWHY leads the tissue response towards an M2-driven reaction, which has assumed to be correlated with tissue healing [62]. Thus, a higher level of bone regeneration might have been induced after the time point analyzed in the present study.…”

Cellular backpacks for macrophage immunotherapy

“…While the backpacks described here bind to macrophage surfaces, other designs can be conceived to attach to other circulatory cells with higher chemotactic sensitivity (17,18,55). Also, a range of immunomodulatory payloads can be considered, including those that facilitate adaptive immune responses toward a backpack-based vaccine (52) or promote anti-inflammatory phenotypes to aid in tissue regeneration or repair for autoimmune diseases (56,57). PDMS template preparation PDMS templates were prepared by soft lithography using methods similar to those described previously (16).…”