Requirement of Myeloid Cells for Axon Regeneration

Barrette, Benoit; Hébert, Marc-André; Filali, Mohammed; Lafortune, Kathleen; Vallières, Nicolas; Gowing, Genevíève; Julien, Jean‐Pierre; Lacroix, Steve

doi:10.1523/jneurosci.1447-08.2008

Cited by 220 publications

(197 citation statements)

References 61 publications

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“…both models of inflammatory pain, we treated CD11b-TK transgenic mice with the nucleoside analog ganciclovir (GCV). The myeloid-specific gene CD11b in these mice drives a mutant form of the suicidal Herpes simplex virus 1 thymidine kinase gene (HSV1-TK mt-30 ), and HSV1-TK mt-30 phosphorylates GCV to inhibit DNA synthesis (30,31), ablating all proliferating transgene positive cells. We found that this treatment resulted in a specific loss of proliferating CD11b + Ly6G − myeloid cells, but not of CD11b + Ly6G + neutrophils (Fig.…”

Section: Resultsmentioning

confidence: 99%

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Ghasemlou

Chiu

Julien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

157

135

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Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund's adjuvant (CFA) as a model of adjuvant-and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G + CD11b + neutrophils and T-cell receptor (TCR) β + T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b + Ly6G − myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2 + Ly6C hi ) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b + Ly6G − myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation.pain | inflammation | cytokines | monocytes | macrophages

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Section: Resultsmentioning

confidence: 99%

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Ghasemlou

Chiu

Julien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

157

135

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“…Clearance of myelin debris is an important part of the regenerative response, as myelin contains axon outgrowth inhibitors and delayed myelin clearance is associated with impaired axon regeneration [87]. There is evidence that NRG1 may act as an early signal between damaged axons and SCs, promoting myelin breakdown [80].…”

Section: Endogenous Nrg1 May Have a Role In The Early Events Of Wallementioning

confidence: 99%

The Role of Neuregulin-1 In the Response To Nerve Injury

Fricker

Bennett

2011

Future Neurol.

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Axons and Schwann cells exist in a highly interdependent relationship: damage to one cell type invariably leads to pathophysiological changes in the other. Greater understanding of communication between these cell types will not only give insight into peripheral nerve development, but also the reaction to and recovery from peripheral nerve injury. The type III isoform of neuregulin-1 (NRG1) has emerged as a key signaling factor that is expressed on axons and, through binding to erbB2/3 receptors on Schwann cells, regulates multiple phases of their development. In adulthood, NRG1 is dispensable for the maintenance of the myelin sheath; however, this factor is required for both axon regeneration and remyelination following nerve injury. The outcome of NRG1 signaling depends on interactions with other pathways within Schwann cells such as Notch, integrin and cAMP signaling. In certain circumstances, this signaling pathway may be maladaptive; for instance, direct binding of Mycobacterium leprae onto erbB2 receptors produces excessive activation and can actually promote demyelination. Attempts to modulate this pathway in order to promote nerve repair will therefore need to give consideration to the exact isoform used, as well as how it is processed and the context in which it is presented to the Schwann cell. Keywordsneuregulin-1; neuropathy; peripheral nerve injury; regeneration; remyelination; repair; Schwann cell Peripheral nerve injury causes significant morbidity and reduced quality of life as a consequence of weakness, sensory loss and neuropathic pain. In total, 6% of the elderly population suffer from peripheral neuropathy [1], which can be caused by metabolic diseases such as diabetes, inherited genetic disorders such as Charcot-Marie-Tooth disease, infectious and inflammatory disorders including Guillan-Barré syndrome and traumatic injury to the nerve (which alone effects up to 300,000 people in Europe per year [1,2]). In contrast to the CNS, peripheral nerves have a significant regenerative capacity [3]; however, in patients, regeneration and the clinical outcome are often poor. Axons regenerate at a rate of approximately 1 mm per day, depending on the site of the lesion. There may be a delay of months if not years before the target zone is re-innervated, and by this time, the target organ and supporting cells may have irreversibly changed, becoming much less receptive to reinnervation. The current approaches to peripheral nerve repair following nerve transection are either to surgically suture the nerve or to bridge the gap between the two cut ends. Financial & competing interests disclosureThe authors have no other rel evant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Europe PMC Funders Group NRGs & the PNSNRGs Neuregulins are a family of growth factors en...

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“…At presymptomatic time points (i.e., weeks 9-12), focal activation occurs for PNS macrophages and spinal cord microglia. Following clinical onset (i.e., weeks [12][13][14][15][16][17][18][19], activation of innate immunity becomes widespread in both tissues as indicated by FACS and histological analysis.…”

Section: Macrophage Activation Occurs Throughout the Peripheral Nervousmentioning

confidence: 99%

“…Mutant SOD1 also induces defects in peripheral axon transport, which may be a primary determinant of motor neuron death (13). In acute models of PNS injury, myeloid cells have been shown to mediate the processes of myelin clearance and subsequent axon regeneration (14). Whether and how the immune system participates in motor axon loss during ALS disease progression remains unexplored.…”

mentioning

confidence: 99%

Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice

Chiu

Phatnani

Kuligowski

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

177

176

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During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1؉ macrophages throughout the PNS in mutant SOD1 G93A and SOD1 G37R transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice.innate immunity ͉ macrophage ͉ peripheral nervous system ͉ neuroimmunology ͉ amyotrophic lateral sclerosis

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Requirement of Myeloid Cells for Axon Regeneration

Cited by 220 publications

References 61 publications

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

The Role of Neuregulin-1 In the Response To Nerve Injury

Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice

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Requirement of Myeloid Cells for Axon Regeneration

Cited by 220 publications

References 61 publications

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

The Role of Neuregulin-1 In the Response To Nerve Injury

Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice

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Product

Resources

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CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity