IL-17 Control of Cutaneous Immune Homeostasis.

IL-17 is widely recognized for its roles in host defense and inflammatory disorders. However, it has become clear that IL-17 is also an essential regulator of barrier tissue physiology. Steady-state microbe sensing at the skin surface induces low-level IL-17 expression that enhances epithelial integrity and resists pathogens without causing overt inflammation. Recent reports describe novel protective roles for IL-17 in wound healing and counteracting physiologic stress; however, chronic amplification of these beneficial responses contributes to skin pathologies as diverse as fibrosis, cancer, and autoinflammation. In this paper, we discuss the context-specific roles of IL-17 in skin health and disease and therapeutic opportunities.

Hydrogel crosslinking modulates macrophages, fibroblasts, and their communication, during wound healing.

Biomaterial wound dressings, such as hydrogels, interact with host cells to regulate tissue repair. This study investigates how crosslinking of gelatin-based hydrogels influences immune and stromal cell behavior and wound healing in female mice. We observe that softer, lightly crosslinked hydrogels promote greater cellular infiltration and result in smaller scars compared to stiffer, heavily crosslinked hydrogels. Using single-cell RNA sequencing, we further show that heavily crosslinked hydrogels increase inflammation and lead to the formation of a distinct macrophage subpopulation exhibiting signs of oxidative activity and cell fusion. Conversely, lightly crosslinked hydrogels are more readily taken up by macrophages and integrated within the tissue. The physical properties differentially affect macrophage and fibroblast interactions, with heavily crosslinked hydrogels promoting pro-fibrotic fibroblast activity that drives macrophage fusion through RANKL signaling. These findings suggest that tuning the physical properties of hydrogels can guide cellular responses and improve healing, offering insights for designing better biomaterials for wound treatment.

Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing.

Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Here, we examine the role of the mechanically activated cation channel Piezo1 in macrophage polarization and sensing of microenvironmental stiffness. We show that macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Additionally, macrophages expressing the transgenic Ca2+ reporter, Salsa6f, reveal that Ca2+ influx is dependent on Piezo1, modulated by soluble signals, and enhanced on stiff substrates. Furthermore, stiffness-dependent changes in macrophage function, both in vitro and in response to subcutaneous implantation of biomaterials in vivo, require Piezo1. Finally, we show that positive feedback between Piezo1 and actin drives macrophage activation. Together, our studies reveal that Piezo1 is a mechanosensor of stiffness in macrophages, and that its activity modulates polarization responses.

YAP-mediated mechanotransduction tunes the macrophage inflammatory response.

Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.

Extracellular Matrix-Based Strategies for Immunomodulatory Biomaterials Engineering.

The extracellular matrix (ECM) is a complex and dynamic structural scaffold for cells within tissues and plays an important role in regulating cell function. Recently it has become appreciated that the ECM contains bioactive motifs that can directly modulate immune responses. This review describes strategies for engineering immunomodulatory biomaterials that utilize natural ECM-derived molecules and have the potential to harness the immune system for applications ranging from tissue regeneration to drug delivery. A top-down approach utilizes full-length ECM proteins, including collagen, fibrin, or hyaluronic acid-based materials, as well as matrices derived from decellularized tissue. These materials have the benefit of maintaining natural conformation and structure but are often heterogeneous and encumber precise control. By contrast, a bottom-up approach leverages immunomodulatory domains, such as Arg-Gly-Asp (RGD), matrix metalloproteinase (MMP)-sensitive peptides, or leukocyte-associated immunoglobulin-like receptor-1(LAIR-1) ligands, by incorporating them into synthetic materials. These materials have tunable control over immune cell functions and allow for combinatorial approaches. However, the synthetic approach lacks the full natural context of the original ECM protein. These two approaches provide a broad range of engineering techniques for immunomodulation through material interactions and hold the potential for the development of future therapeutic applications.

Harnessing macrophage plasticity for tissue regeneration.

Macrophages are versatile and plastic effector cells of the immune system, and contribute to diverse immune functions including pathogen or apoptotic cell removal, inflammatory activation and resolution, and tissue healing. Macrophages function as signaling regulators and amplifiers, and influencing their activity is a powerful approach for controlling inflammation or inducing a wound-healing response in regenerative medicine. This review discusses biomaterials-based approaches for altering macrophage activity, approaches for targeting drugs to macrophages, and approaches for delivering macrophages themselves as a therapeutic intervention.