Anat Cell Biol.  2013 Mar;46(1):1-7. 10.5115/acb.2013.46.1.1.

The immune modulating properties of the heat shock proteins after brain injury

• Kim JY
• Yenari MA

• KMID: 2046752
• DOI: http://doi.org/10.5115/acb.2013.46.1.1

Abstract

Inflammation within the central nervous system often accompanies ischemia, trauma, infection, and other neuronal injuries. The immune system is now recognized to play a major role in neuronal cell death due to microglial activation, leukocyte recruitment, and cytokine secretion. The participation of heat shock proteins (Hsps) in the immune response following in brain injury can be seen as an attempt to correct the inflammatory condition. The Hsps comprise various families on the basis of molecular size. One of the most studied is Hsp70. Hsp70 is thought to act as a molecular chaperone that is present in almost intracellular compartments, and function by refolding misfolded or aggregated proteins. Hsps have recently been studied in inflammatory conditions. Hsp70 can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. In this review, we will focus on underlying inflammatory mechanisms and Hsp70 in acute neurological injury.

Keyword

Heat shock proteins; Brain injury; Molecular chaperones; Immune system; Anti-inflammation

MeSH Terms

Brain
Brain Injuries
Cell Death
Central Nervous System
Heat-Shock Proteins
Hot Temperature
Humans
Immune System
Inflammation
Ischemia
Leukocytes
Molecular Chaperones
Neurons
Proteins
Heat-Shock Proteins
Molecular Chaperones
Proteins

Figure

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  Fig. 1 The mechanism of heat shock protein (Hsp70) modulation adaptive and innate immune signaling pathways following brain injury. There are multiple sites where Hsp70 has been shown to play roles in modulating the inflammatory response. Many extracellular functions appear to potentiate immune responses, whereas intracellular mechanisms appear to be anti-inflammatory. Extracellular Hsp70 complexed with peptides interacts with the CD91 receptor to enhance antigen presentation, while peptidefree Hsp70 acts has been shown to be a ligand for Toll-like receptors (TLR) 2 and 4 to increase immune responses. Interestingly, Hsp70 can also interrupt pro-matrix metalloproteinases (MMPs) cleavage to an active form and lead to reduction in extracellular matrix disruption, which in turn may reduce immune signaling. In a typical immune cell, cytosolic Hsp70 tends to inhibit immune responses. It is tethered in the cytosol by heat shock factor (HSF), but stress and inflammatory signals lead to promote dissociation of Hsp90 from the HSF and phosphorylation (pHSF) allowing pHSF to enter the nucleus, resulting in increased production of Hsp70. Cytosolic Hsp70, presumably through its chaperone activities, has been shown to interact with and inhibit various components of the pro-inflammatory transcription factor nuclear factor kappa B (NF-kB). IKK, IkB, and NF-kB subunits have all been documented to interact with Hsp70. iNOS, inducible nitric oxide synthase.

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