In vivo delivery of heat shock protein 70 accelerates wound healing by up-regulating macrophage-mediated phagocytosis.
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.
Kovalchin
Joseph T
JT
Center for Immunotherapy, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
Wang
Ruibo
R
Wagh
Mihir S
MS
Azoulay
Jason
J
Sanders
Melinda
M
Chandawarkar
Rajiv Y
RY
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010587:Phagocytosis / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D014945:Wound Healing / Q000187:drug effects*
D018932:Chemokine CCL2; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; C053387:endoplasmin