Dendritic Cell-Mediated Phagocytosis but Not Immune Activation Is Enhanced by Plasmin

Abstract

Removal of dead cells in the absence of concomitant immune stimulation is essential for tissue homeostasis. We recently identified an injury-induced protein misfolding event that orchestrates the plasmin-dependent proteolytic degradation of necrotic cells. As impaired clearance of dead cells by the innate immune system predisposes to autoimmunity, we determined whether plasmin could influence endocytosis and immune cell stimulation by dendritic cells – a critical cell that links the innate and adaptive immune systems. We find that plasmin generated on the surface of necrotic cells enhances their phagocytic removal by human monocyte-derived dendritic cells. Plasmin also promoted phagocytosis of protease-resistant microparticles by diverse mouse dendritic cell sub-types both in vitro and in vivo. Together with an increased phagocytic capacity, plasmin-treated dendritic cells maintain an immature phenotype, exhibit reduced migration to lymph nodes, increase their expression/release of the immunosuppressive cytokine TGF-β, and lose their capacity to mount an allogeneic response. Collectively, our findings support a novel role for plasmin formed on dead cells and other phagocytic targets in maintaining tissue homeostasis by increasing the phagocytic function of dendritic cells while simultaneously decreasing their immunostimulatory capacity consistent with producing an immunosuppressive state.

Physicochemical properties that control protein aggregation also determine whether a protein is retained or released from necrotic cells

“…It remains to be determined whether other NCC-resistant proteins are released from necrotic cells, but this seems highly likely (for reasons provided below with figures 4 and 5). The capacity of FUS and other NCC-resistant proteins to act as paracrine communicators of injury should now be assessed, especially given the influence of NCC on the proteolytic [10,20] and phagocytic [21] removal of dead cells. It will also be interesting to see if FUS released from necrotic cells has a role during FUS-mediated amyotrophic lateral sclerosis [37].…”

“…NCC causes many intracellular proteins, including actin, tubulin, GAPDH and HSP90β, to convert from a soluble form into high-molecular-weight insoluble species [10]. In vitro and in vivo data show that NCC-aggregated proteins promote activation of the extracellular protease plasmin on the surface of dead cells [10,20,21]. Surface-bound plasmin then initiates two forms of clearance: direct proteolytic degradation of dead cells [10,20] and signalling nearby dendritic cells to increase their phagocytic capacity [21].…”

Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis

“…Plasmin has been described as a promoter of inflammation, yet recent findings suggest a more complex role in the modulation of immunity, including its ability to induce a tolerogenic phenotype to dendritic cells by reducing their capacity to induce an allogeneic immune response . Curiously, studies using plasminogen‐deficient mice have reported both reduced and exacerbated inflammatory responses, depending on the disease model: plasmin(ogen) deficiency can be deleterious in models of wound healing, yet protective in models of lipopolysaccharide‐induced and experimental autoimmune encephalomyelitis‐induced neuroinflammation indicating that plasminogen is needed to exert a complete inflammatory response.…”

“…It has been implicated in inflammatory processes by direct interaction with proinflammatory and anti‐inflammatory mediators as well as various leukocyte subsets, by binding to cell‐surface plasminogen receptors and inducing intracellular signaling . In contrast, monocyte‐derived dendritic cells treated with plasmin exhibit enhanced phagocytic capacity, yet a reduced ability to migrate to the draining lymph nodes and to mount an allogeneic immune response …”

Angry macrophages patrol for fibrin

“…In addition, plasmin activity promotes phagocytosis by both macrophages 4 and dendritic cells. 5 This involves both recognition of prey and direct effects on engulfment of prey, events which are regulated by plasmin-mediated activation of intracellular signaling pathways that regulate expression of major genes involved in phagocytosis. 4 There may be an analogous mechanism for cellular fibrin uptake.…”