In vivo delivery of heat shock protein 70 accelerates wound healing by up‐regulating macrophage‐mediated phagocytosis

Abstract

Injury causes tissue breakdown, which releases large quantities of intracellular contents into the extracellular space. Some of these materials are well-established activators of the immune system and include heat shock proteins (HSPs), uric acid, nucleotides, High Mobility Group Box-1 protein (HMGB-1), and DNA. Here, we show that in vivo delivery of HSPs into BALB/cJ mice with full-thickness wounds accelerates the rate of wound closure by 60% as compared with control-treated mice. The onset is rapid and the effect is sustained, dose dependent, and protein specific. Adoptive transfer of RAW264 macrophages pretreated with HSP70 into naïve recipients with a wound transfers the HSP-mediated effect on the rate of wound closure. Further, we demonstrate that part of the mechanism by which HSP70 accelerates wound closure is through the stimulation of macrophage-mediated phagocytosis of wound debris. Disabling the HSP70-mediated enhancement of phagocytosis abrogates the HSP-mediated acceleration of the healing process. These findings create two opportunities: one, therapeutic, wherein HSP70 could be used in the clinical management of wounds; and two, pathophysiologic, to decode signals by which the host defenses recognize and respond to injury.

Propofol inhibits pressure-stimulated macrophage phagocytosis via the GABAA receptor and dysregulation of p130cas phosphorylation

“…Increasing the recruitment of monocytes or macrophages accelerates wound healing (22,60). Inhibition of macrophage phagocytosis with antimacrophage serum also slows wound healing (31), whereas administration of heat shock protein 70, which stimulates macrophage phagocytosis (60), accelerates wound healing (29). These reports suggest that macrophage phagocytosis is essential for normal wound healing.…”

“…Leibovich and Ross (31) reported that elimination of local macrophages at the wound site impairs the wound-healing process, and impaired macrophage phagocytic function also leads to a defect in wound healing (54). Furthermore, macrophages might be activated at the wound site, where a large amount of the intracellular content is released into the extracellular space (29), and these macrophages produce cytokines, growth factors, and chemokines, which promote further recruitment of immune cells (7,41). These tissue macrophages may play important roles in wound healing immediately after surgery.…”

“…This process begins early after injury, although it may persist for days thereafter. Depletion of macrophages, but not neutrophils, from wound sites impairs wound debridement and delays wound healing (31), whereas enhancement of macrophage phagocytosis by administration of heat shock protein 70 accelerates wound healing in mice (29).…”

Immunolocalization of heat shock proteins 27 and 47 during repair of induced oral ulcers

“…They are a part of the chaperone group that is expressed intracellularly under normal conditions. Expression levels are increased during heat shock (2,3) and by other types of stress, such as infection, inflammation, recovery from anoxia, and glucose starvation (3). As cytoprotective chaperones, Hsps act in the conformational change of other proteins, the formation of protein multicomplexes, thermotolerance, and the prevention of protein aggregation.…”

“…Hsp expression is increased during the normal reparative process and diminished during the chronic reparative process (2,3). Hypotheses regarding marked expression of Hsp during normal repair highlight the fact that, during healing, cells are exposed to a sequence of injuries, such as dehydration, alterations in the partial pressure of the oxygen and carbon dioxide, transient ischemia, and high production of reactive oxygen metabolites (5).…”