Stimulation of FcγRI on Primary Sensory Neurons Increases Insulin-Like Growth Factor-I Production, Thereby Reducing Reperfusion-Induced Renal Injury in Mice

Abstract

Biological role(s) of FcγRI on mouse primary sensory neurons are not fully understood. Sensory neuron stimulation increases insulin-like growth factor-I (IGF-I) production, thereby reducing ischemia/reperfusion (I/R)-induced tissue injury in mice. In this study, we examined whether the Fc fragment of IgG (IgGFc) increases IGF-I production through sensory neuron stimulation, thereby reducing I/R-induced renal injury in mice. IgGFc increased the calcitonin-gene–related peptide (CGRP) release and cellular cAMP levels in dorsal root ganglion neurons isolated from wild-type (WT) mice, whereas, native IgG did not. Pretreatment with anti-FcγRI Ab, a protein kinase A inhibitor KT5710, and a phospholipase A2 inhibitor 4-bromophenylacyl bromide inhibited these effects induced by IgGFc. Administration of IgGFc enhanced increases of renal tissue levels of CGRP and IGF-I and reduced I/R-induced renal injury in WT mice. Increases of renal tissue level of caspase-3, renal accumulation of neutorphils, and renal tubular apoptosis were inhibited by administration of IgGFc in WT mice subjected to renal I/R. Pretreatment with anti–IGF-I Ab completely reversed these effects induced by IgGFc in WT mice. Administration of native IgG did not show any effects in WT mice subjected to renal I/R. None of the effects observed in WT mice was seen after IgGFc administration in CGRP-knockout mice and denervated WT mice. These observations suggest that activation of FcγRI by IgGFc may stimulate sensory neurons, thereby promoting IGF-I production, contributing to reduction of the reperfusion-induced renal injury via attenuation of inflammatory responses in mice.

Neuronal Fc-gamma receptor I mediated excitatory effects of IgG immune complex on rat dorsal root ganglion neurons

“…A previous study also demonstrated that the activation of FcγRI by the Fc fragment of IgG (IgG Fc) at the higher dose induced smaller changes in CGRP release and cAMP levels in DRG neurons, as compared to the lower dose of IgGFc (Harada et al, 2010). One possible reason is that the higher concentration of IC mixtures contain a relative larger amount of monometric IgG that competitively blocks the effects of FcγRI on the neuronal surface (Nimmerjahn and Ravetch, 2006).…”

Crosstalk between the nociceptive and immune systems in host defence and disease

“…For example, sensory neurons express high-affinity receptors for IgG (termed FcγRIII) that bind to the Fc region of IgG, particularly in the context of IgG-antigen complexes 58 . Such binding can lead to neuropeptide release by sensory neurons and, in the context of renal reperfusion injury, increased expression of insulin-like growth factor 1 (IGF1), which is protective 59 .…”

Aggravation of post-ischemic liver injury by overexpression of insulin-like growth factor binding protein 3

“…Next, to assess the role of IGFBP-3 in liver I/R injury, we injected C57BL/6 mice intravenously with 1 × 109 pfu of AdLacZ, AdIGFBP-3, or AdIGFBP-3 GGG virus (Fig. S1A).…”

“…The results revealed that IGFBP-3 worsened morphometric tissue damage, aminotransferase release, and inflammatory responses with concomitant changes in biochemical parameters following I/R. Of interest, IGF-1 administration protects several organs against I/R injury and improves functional recovery89101112. To exclude the possible involvement of IGF-l, we used an IGFBP-3 mutant with disrupted binding affinity for IGF-1 due to mutations in the binding site.…”

“…IGF-1 has a well-established protective effect against I/R injures in liver8, kidney9, heart1011, and brain12. IGF-1 is transported to its action site by binding to six structurally related IGF binding proteins (IGFBPs).…”