Expression of JE (Monocyte Chemoattractant Protein-1) Is Induced by Sciatic Axotomy in Wild Type Rodents but Not in C57BL/Wld S Mice

Abstract

Recruitment of hematogenous myelomonocytic cells into injured peripheral nerve is essential for axonal regeneration. The monocyte chemoattractant protein-1 (JE) and melanoma growth stimulatory activity/gro (KC) "immediate early" gene products may be important in this process as these proteins are potent chemoattractants for macrophages and neutrophils, respectively. To test this hypothesis, we examined JE and KC activation in rat sciatic nerve 0-30 days after surgical transection. RT-PCR and in situ hybridization analyses of JE and KC expression demonstrates these mRNAs are present in injured nerve, first being expressed by a cellular subpopulation within the zone of trauma by 1.5 hours after injury. By 16 hours posttransection a subpopulation of JE-positive endoneurial cells is found in the proximal stump and throughout the distal nerve segment, with maximal mRNA accumulation occurring 1 day after injury and expression persisting to 18 days postaxotomy, a period preceding and coincident with macrophage infiltration. In contrast, by 3 days postaxotomy KC expression is markedly diminished, consistent with the limited neutrophilic response to nerve injury. JE expression was also examined in C57BL/Wld(s) mice, which have delayed Wallerian degeneration associated with a failure of macrophage recruitment, and their parental C57BL/6J strain. Although JE mRNA is inducible in sciatic nerve from C57BL/6J mice, these transcripts are undetectable in injured nerve from C57BL/Wld(s) mice. Our findings suggest that activation of the JE locus is at least partially responsible for macrophage invasion of injured peripheral nerve. Furthermore, defective postaxotomy macrophage recruitment in C57BL/Wld(s) mice may involve a failure of JE induction.

Toll-Like Receptor Signaling Is Critical for Wallerian Degeneration and Functional Recovery after Peripheral Nerve Injury

“…For this experiment, mice were killed at 1.5 and 24 h after lesion. These two time points were selected based on a previous study, which showed that MCP-1 mRNA is already expressed at 1.5 h after sciatic nerve lesion, with maximal expression occurring at 24 h (Carroll and Frohnert, 1998). As expected, we found no hybridization signal for any of the proinflammatory molecules analyzed (i.e., IL-1␤, MCP-1, TNF, IFN␤, and iNOS) on sciatic nerve sections obtained from noninjured mice.…”

“…However, the fact that MCP-1 expression precedes the appearance of axonal and myelin debris in the injured PNS [the first signs of axonal fragmentation distal to the lesion are typically seen after 36 -44 h after injury (Beirowski et al, 2005)] does not support the possibility that necrotic cells are responsible for initiating innate immune responses during WD. Nevertheless, because MCP-1 expression is considerably delayed in peripheral nerves of Wld s mutant mice (Carroll and Frohnert, 1998), and because early cytokine expression after nerve injury can be blocked by pretreatment with a calpain inhibitor (calpain is known to disassemble cytoskeletal proteins after axonal damage) (Uceyler et al, 2007), it is tempting to speculate that the endogenous ligand(s) responsible for TLR activation is released by degenerating axons. In this regard, a study by Willis and Twiss (2006) has recently identified Ͼ100 distinct axonally synthesized proteins, including several HSPs, in lesioned dorsal root ganglion sensory axons.…”

“…Work done with various animal models, including slow WD (Wld s ) mutant mice, has been instrumental in revealing how axonal loss rapidly leads to a series of responses implicating non-neuronal cells, including the dedifferentiation, proliferation, and activation of Schwann cells; the activation of resident endoneurial macrophages; and the recruitment of immune cells from the periphery Lunn et al, 1989;Brown et al, 1991;Mueller et al, 2003). Of particular interest are studies that linked these cellular responses to the secretion of specific proinflammatory cytokines and chemokines Reynolds and Woolf, 1993;Fu and Gordon, 1997;Carroll and Frohnert, 1998;Liefner et al, 2000;Siebert et al, 2000;Perrin et al, 2005).…”

“…We recently demonstrated that proinflammatory cytokines/chemokines interleukin-1␤ (IL-1␤), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1␣ (MIP-1␣) regulate myelin debris clearance after sciatic nerve lesion in mice (Perrin et al, 2005). Several inflammatory cytokines/chemokines are produced as early as 1 h after peripheral nerve lesion, with expression levels peaking at ϳ24 h (Carroll and Frohnert, 1998;Shamash et al, 2002;Stoll et al, 2002;Perrin et al, 2005). Studies have revealed that endoneurial cells such as Schwann cells and resident macrophages are responsible for the initial production of cytokines and chemokines in injured peripheral nerves (Taskinen and Roytta, 2000;Subang and Richardson, 2001;Shamash et al, 2002).…”

A comparison of the changes in the non‐neuronal cell populations of the superior cervical ganglia following decentralization and axotomy

“…Nevertheless, the differences we have found between decentralization and axotomy in the macrophage population of the SCG argues against such a systemic effect playing a major role in the macrophage population in the SCG. In addition, recent studies have demonstrated that monocyte chemoattractant protein (MCP-1) is increased within the SCG after axotomy (Schreiber et al, 1997;, as it is within the degenerating stump of the transected sciatic nerve (Carroll and Frohnert, 1998;Toews et al, 1998: Subang andRichardson, 2001). We are currently examining whether this peptide plays a necessary role in the infiltration of macrophages into the SCϪ/Ϫ, using MCP-1 null mutant mice.…”