Macrophage Response to Peripheral Nerve Injury: The Quantitative Contribution of Resident and Hematogenous Macrophages

Abstract

SUMMARY:Whereas local microglial cells of the CNS rapidly respond to injury, little is known about the functional role of resident macrophages of the peripheral nervous system in nerve pathology. Using bone marrow chimeric rats, we recently identified individual resident endoneurial macrophages that rapidly became activated after nerve injury. However, the extent of local macrophage activation and its quantitative contribution to the total macrophage response is unknown. We now have created chimeric mice by transplanting bone marrow from green fluorescent protein (GFP)-transgenic mice into irradiated wild-type mice, allowing easy differentiation and quantification of hematogenous and resident endoneurial macrophages. After sciatic nerve crush injury, both GFP Ϫ and GFP ϩ resident macrophages, the latter having undergone physiological turnover from the blood before injury, rapidly underwent morphological alterations and increased in number. Proliferating GFP Ϫ and GFP ϩ resident macrophages were abundant and peaked 3 days after injury. A major lesion-induced influx of hematogenous macrophages with a disproportionate increase of GFP ϩ macrophages was not observed until Day 4. Throughout all time points examined, GFP Ϫ resident macrophages were strikingly frequent, reaching maximum numbers 9.5-fold above baseline. There was also a notable proportion of GFP Ϫ resident endoneurial macrophages phagocytosing myelin and expressing major histocompatibility complex class II. Our results demonstrate for the first time that the rapid response of resident endoneurial macrophages to nerve injury is quantitatively important and that local macrophages contribute significantly to the total endoneurial macrophage pool during Wallerian degeneration. (Lab Invest 2003, 83:175-185).

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

“…Previous studies following axotomy of primary afferent sensory nerves has been shown to promote the activation and migration of macrophages within the peripheral nerve (Myers et al, 1996;Tofaris et al, 2002;Abbadie et al, 2003) and associated DRG (Hu & McLachlan, 2002). The increased number of macrophages observed may be due to proliferation of resident macrophages or due to infiltration of hematogeneous macrophages into the DRG (Mueller et al, 2003). Functionally, macrophage activation within the DRG and peripheral nerve following peripheral nerve injury is known to help remove degenerating neuronal debris and myelin as well as contribute to subsequent regeneration (Lu and Richardson 1993, Perry and Brown 1992, Hu and McLachlan 2002.…”

Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature

“…Nerve fibers distal to the injury undergo rapid degeneration, with only the sheath remaining to guide regenerative axon sprouting; some retraction of proximal fibers also occurs. At the cellular level, the distal degeneration is dominated by a massive accumulation of macrophages, peaking between days 7 and 14 and then gradually clearing (25). At the molecular level, there is an increase in perineural levels of proinflammatory mediators such as TNF-α, IL-1β, CCL2, and CCL3, even before the expansion of the macrophage population, i.e., at days 1-3 (26,27).…”

Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors

“…In the periphery, the proinflammatory cytokines IL-1␣ and TNF-␣ released by macrophages contribute to behavioral hypersensitivity after peripheral nerve injury (23)(24)(25). Stimulation of the vagus nerve reduces TNF-␣ production by macrophages in response to bacterial endotoxin in wild-type mice, but not in ␣7 nAChR knockout mice (22).…”