Further evidence for a crucial role of resident endoneurial macrophages in peripheral nerve disorders: Lessons from acrylamide‐induced neuropathy

Abstract

Endoneurial macrophages are crucially involved in the pathogenesis of neuropathies. Historically, the macrophage response in neuropathies is believed to be of hematogenous origin. However, recent studies could demonstrate an intrinsic generation of the early macrophage response by resident endoneurial macrophages after traumatic nerve injury and in a model of hereditary neuropathy. We hypothesized that the local macrophage response might suffice to generate an appropriate macrophage response in mild neuropathies, supplemented by infiltrating macrophages only in severe nerve pathology. To clarify this assumption, we investigated the macrophage response in acrylamide-induced neuropathy as a model of a slowly progressive neuropathy with a defined onset. We induced the neuropathy in bone marrow chimeric mice carrying green fluorescent protein transgenic bone marrow, allowing the differentiation of resident (GFP(-)) and invading hematogenous endoneurial (GFP(+)) macrophages. Quantification of GFP(-) and GFP(+) endoneurial macrophages in the sciatic nerve revealed an increase only of resident macrophages in proximal parts, whereas in distal parts a minor additional influx of hematogenous macrophages was observed. The immunohistochemical profile of GFP(-) and GFP(+) macrophages was similar but distal GFP(-) macrophages were differentially activated than their GFP(+) counterparts. Characterization of CCR2-deficient mice revealed a function for this chemokine system in attracting hematogenous macrophages but not in generating the intrinsic macrophage response. In conclusion, we provide evidence for a role of resident macrophages in acrylamide-induced neuropathy. Resident endoneurial macrophages intrinsically generate the macrophage response in this slowly progressive neuropathy, which only becomes supplemented by hematogenous macrophages in distal areas of more pronounced damage.

Resident Macrophages in Muscle Contribute to Development of Hyperalgesia in a Mouse Model of Noninflammatory Muscle Pain

“…In animals with nerve injury, they show activation of resident macrophages early before the influx of hematogenous macrophages, proliferation of resident macrophages throughout a 28-day sampling period, and a slow turnover of resident macrophages in nerve suggesting resident macrophages play an active role in the cellular events after peripheral insult. Further, activation and proliferation of resident macrophages occurs in mild pathophysiological conditions, and hematogenous macrophages are supplemented only in more severe pathological processes [37–39]. Our study showed that acid injection produced a small increase in the number of macrophages in muscle.…”

Visualization of Chemokine Receptor Activation in Transgenic Mice Reveals Peripheral Activation of CCR2 Receptors in States of Neuropathic Pain

“…Indeed, it is possible that MCP1 may act at multiple sites and that the precise nature of its involvement may differ in different types of pain. Generally speaking, however, it is thought that Schwann cells and/or endoneurial fibroblasts in injured axons upregulate MCP1, which then attracts macrophages into the nerve (Carroll and Frohnert, 1998; Toews et al, 1998; Tofaris et al, 2002; Müller et al, 2008). Infiltrating macrophages may then secrete inflammatory molecules that sensitize the nerve.…”

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

“…To evaluate differences in the morphology of Aβ plaques between APP/ PS1 and APP/PS1/Cxcr3 -/-mice, we used the shape descriptors plugin (form factor, defined as 4π × area/perimeter 2 ) using ImageJ software. The form factor is usually used as a parameter of macrophage activation by means of morphology (87). The form factor varies between 0 (a 2-dimensional line) and 1 (a circle).…”