AlphaB-crystallin (αBC) is a small heat shock protein that is constitutively expressed by peripheral nervous system (PNS) axons and Schwann cells. To determine what role this crystallin plays after peripheral nerve damage, we found that loss of αBC impaired remyelination, which correlated with a reduced presence of myelinating Schwann cells and increased numbers of nonmyelinating Schwann cells. The heat shock protein also seems to regulate the cross-talk between Schwann cells and axons, because expected changes in neuregulin levels and ErbB2 receptor expression after PNS injury were disrupted in the absence of αBC. Such dysregulations led to defects in conduction velocity and motor and sensory functions that could be rescued with therapeutic application of the heat shock protein in vivo. Altogether, these findings show that αBC plays an important role in regulating Wallerian degeneration and remyelination after PNS injury.T he robust regenerative capacity of the damaged peripheral nervous system (PNS) is partly determined by cellular and molecular events that occur in the nerve segment distal to the injury site (1). For instance, during Wallerian degeneration, influx of calcium into the damaged nerve within 12-24 h of PNS injury activates proteases (2) that result in cytoskeletal breakdown and subsequent disintegration of the axon membrane. This axon degeneration is then followed by breakdown of the myelin sheath within 2 d (3). Schwann cells, the glial cells that characterize the PNS, subsequently undergo a number of reactive physiological changes that benefit the damaged axon. Within 48 h of peripheral nerve damage, myelinating Schwann cells decrease their expression of myelin proteins, such as myelin basic protein (MBP), peripheral myelin protein 22, and protein 0 (P0) (4), and along with their nonmyelinating counterparts, revert to a nonmyelinating phenotype (4). At ∼3-4 d postinjury, the dedifferentiated Schwann cells proliferate (5-7) and align within the basal lamina to form bands of Büngner that provide a structural and trophic supportive substrate for regenerating axons. These Schwann cells secrete neurotrophic factors that provide trophic sustenance to damaged neurons until they reestablish contact with their targets (8) and produce extracellular matrix molecules that encourage and guide outgrowing axons (9), whereas secretion of chemokines is thought to mediate the infiltration of blood-derived macrophages, which along with Schwann cells, phagocytose myelin debris and its associated axon growth inhibitors (9). Finally, based on the level of neuregulin 1 Types I and III on Schwann cells and axons, respectively, and their binding to their cognate receptors ErbB2/ ErbB3 on Schwann cells, these glia will revert to a myelinating or ensheathing phenotype on contact with regrowing axons (10). Altogether, these morphological and physiological changes in Schwann cells create an environment that encourages longdistance axon growth.In humans, however, regrowth of damaged peripheral nerves is often incomplete, wh...

Background Inflammation constitutes both positive and negative aspects to recovery following peripheral nerve injury. Following damage to the peripheral nervous system (PNS), immune cells such as macrophages play a beneficial role in creating a supportive environment for regrowing axons by phagocytosing myelin and axonal debris. However, a prolonged inflammatory response after peripheral nerve injury has been implicated in the pathogenesis of negative symptoms like neuropathic pain. Therefore, the post-injury inflammation must be carefully controlled to prevent secondary damage while allowing for regeneration. CRYAB (also known as alphaB-crystallin/HSPB5) is a small heat shock protein that has many protective functions including an immunomodulatory role in mouse models of multiple sclerosis, spinal cord injury, and stroke. Because its expression wanes and rebounds in the early and late periods respectively after PNS damage, and CRYAB null mice with sciatic nerve crush injury display symptoms of pain, we investigated whether CRYAB is involved in the immune response following PNS injury. Methods Sciatic nerve crush injuries were performed in age-matched Cryab knockout (Cryab−/−) and wildtype (WT) female mice. Nerve segments distal to the injury site were processed by immunohistochemistry for macrophages and myelin while protein lysates of the nerves were analyzed for cytokines and chemokines using Luminex and enzyme-linked immunosorbent assay (ELISA). Peritoneal macrophages from the two genotypes were also cultured and polarized into pro-inflammatory or anti-inflammatory phenotypes where their supernatants were analyzed for cytokines and chemokines by ELISA and protein lysates for macrophage antigen presenting markers using western blotting. Results We report that (1) more pro-inflammatory CD16/32+ macrophages are present in the nerves of Cryab−/− mice at days 14 and 21 after sciatic nerve crush-injury compared to WT counterparts, and (2) CRYAB has an immunosuppressive effect on cytokine secretion [interleukin (IL)-β, IL-6, IL-12p40, tumor necrosis factor (TNF)-α] from pro-inflammatory macrophages in vitro. Conclusions CRYAB may play a role in curbing the potentially detrimental pro-inflammatory macrophage response during the late stages of peripheral nerve regeneration.

Injury to axons of the central nervous system (CNS) and the peripheral nervous system (PNS) is accompanied by the upregulation and downregulation of numerous molecules that are involved in mediating nerve repair, or in augmentation of the original damage. Promoting the functions of beneficial factors while reducing the properties of injurious agents determines whether regeneration and functional recovery ensues. A number of chaperone proteins display reduced or increased expression following CNS and PNS damage (crush, transection, contusion) where their roles have generally been found to be protective. For example, chaperones are involved in mediating survival of damaged neurons, promoting axon regeneration and remyelination and, improving behavioral outcomes. We review here the various chaperone proteins that are involved after nervous system axonal damage, the functions that they impact in the CNS and PNS, and the possible mechanisms by which they act.

No abstract

No abstract

No abstract

No abstract