Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli

Abstract

Neurotrophins, such as nerve growth factor (NGF) and neurotrophin-3 (NT-3), are essential for development, function, and survival of peripheral sympathetic and sensory neurons. Most eosinophilic leukocytes in the human body are localized in mucosal tissues; however, the roles of eosinophils in human diseases are not fully understood. We found that human eosinophils constitutively express messenger RNA for NGF and NT-3, synthesize and store these proteins intracellularly, and continuously replenish them. Incubation of eosinophils with a transcription inhibitor, actinomycin D, for 8 hours completely depletes intracellular NGF and NT-3. New synthesis of NGF is enhanced by Fc-receptor-mediated stimuli, such as immunoglobulin (Ig)A and IgG immune complexes; in contrast, production of NT-3 is not affected by these stimuli. Notably, supernatants of eosinophils stimulated with IgA immune complex and interleukin 5 promote neurite extension of the PC-12 pheochromocytoma cell line; this effect is abolished by pretreatment of the supernatants with anti-NGF-neutralizing antibody. By enzyme-linked immunosorbent assay, substantial amounts of NGF protein are also detected in the supernatants of stimulated eosinophils. Furthermore, in patients with seasonal allergic rhinitis, the concentrations of NGF in nasal secretions correlate with the magnitudes of eosinophilic inflammation in the airway, suggesting a potential clinical implication of eosinophil NGF. Our observations propose a new pathologic mechanism by which eosinophils may contribute to enhanced neurologic responses in patients with allergic diseases and other eosinophilic disorders. Alternatively, eosinophils may play important roles in maintenance and restoration of homeostatic functions of mucosal tissues through the pleitropic activities of NGF.

The role of the immune system in central nervous system plasticity after acute injury

“…MCs attach to growing neurites (Furuno et al, 2005) where they can synthesize, store and release NGF, thus enhancing axonal sprouting of neuronal networks (Wilhelm et al, 2005). Similarly, eosinophils synthesize specific neurotrophins, including NGF, brainderived neurotrophic factor (BDNF) and neurotrophin (NT)-3, that can be released upon stimulation (Kobayashi et al, 2002) and have major stimulatory effect on neurite outgrowth (Foster et al, 2011). Several in vitro and in vivo experiments have shown that also microglia/macrophages have a major role in axonal regeneration.…”

Prolonged exposure to NT-3 attenuates cholinergic nerve-mediated contractions in cultured murine airways

“…A known source of NT-3 in human airways are eosinophils (Barouch et al, 2000;Kobayashi et al, 2002), whereas BDNF can be derived from macrophages, T-lymphocytes and epithelial cells (Barouch et al, 2000;Braun et al, 1999;Kerschensteiner et al, 1999). However, whether NT-3 or BDNF affects the neural activity and contribute to AHR is not clear (Renz, 2001).…”

Nerve growth factor levels and localisation in human asthmatic bronchi

“…Among these are cells from the immune system, including mast cells [13][14][15][16], eosinophils [17,18], lymphocytes [19,20], monocytes [21] and macrophages [4,22], as well as structural cells, such as fibroblasts, epithelial cells and smooth muscle cells [23][24][25][26][27][28]. Many of these cell types are important participants in the inflammatory condition of the asthmatic airways.…”