Attenuation of MCP-1/CCL2 expression ameliorates neuropathy in a mouse model for Charcot–Marie–Tooth 1X

Abstract

The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been previously shown to be an important mediator of macrophage-related neural damage in models of two distinct inherited neuropathies, Charcot-Marie-Tooth (CMT) 1A and 1B. In mice deficient in the gap junction protein connexin 32 (Cx32def), an established model for the X-chromosome-linked dominant form of CMT (CMT1X), we investigated the role of the chemokine in macrophage immigration and neural damage by crossbreeding the Cx32def mice with MCP-1 knockout mutants. In Cx32def mutants typically expressing increased levels of MCP-1, macrophage numbers were strongly elevated, caused by an MCP-1-mediated influx of haematogenous macrophages. Curiously, the complete genetic deletion of MCP-1 did not cause reduced macrophage numbers in the nerves due to compensatory proliferation of resident macrophages. In contrast, and as already seen in other CMT models, heterozygous deletion of MCP-1 led to reduced numbers of phagocytosing macrophages and an alleviation of demyelination. Whereas alleviated demyelination was transient, axonal damage was persistently improved and even robust axonal sprouting was detectable at 12 months. Other axon-related features were alleviated electrophysiological parameters, reduced muscle denervation and atrophy, and increased muscle strength. Similar to models for CMT1A and CMT1B, we identified MEK-ERK signalling as mediating MCP-1 expression in Cx32-deficient Schwann cells. Blocking this pathway by the inhibitor CI-1040 caused reduced MCP-1 expression, attenuation of macrophage increase and amelioration of myelin- and axon-related alterations. Thus, attenuation of MCP-1 upregulation by inhibiting ERK phosphorylation might be a promising approach to treat CMT1X and other so far untreatable inherited peripheral neuropathies in humans.

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

“…Elevated ErbB3 protein levels were found in the peripheral nerves of CMT1X patients [106], suggesting that abnormal ErbB receptor signaling could contribute to CMT1X pathogenesis. This idea is supported by a recent study showing increased Erk signaling in Schwann cells of Cx32-deficient mice [112], suggesting that dysregulated ErbB receptor signaling may also be involved in CMT1X neuropathy.…”

“…For example, ErbB receptor kinase inhibitor PKI 166 is able to abrogate Mycobacterium leprae -induced ErbB2 and Erk signaling over-activation and demyelination in mice [33]. Mek inhibitor, such as CI-1040 and U0126, has been shown to reduce the augmented Erk signaling and demyelination phenotype in rodent models of CMT1A [27, 107] and CMT1X [112]. In addition, agents such as geldanamycin [121] and ErbB receptor-specific monoclonal antibodies [122–124] that facilitate ErbB receptor endocytosis and degradation could be explored in preclinical studies for treating certain forms of CMT with elevated ErbB levels and augmented Erk signaling (Table 2).…”

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

“…Macrophages were identified in semithin sections at 400× magnification as cells laden with myelin debris, devoid of a basement membrane, and extending small, microvilli-like processes, as described previously (16,46). The macrophage count was calculated as the ratio per 1,000 myelinated fibers, to account for size differences between different roots and nerves.…”

Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury

“…c-Jun, to regulate further target genes including the CCL chemokine Ccl2 [20–22]. Chemokine (C-C motif) ligand 2 (CCL2) is involved in neuron–immune cell interactions during axon regeneration and neuronal degeneration [23–29]. Recently, ATF3 was identified as a core hub present in a RAG network after PNS injury [8].…”