We agree with the comment that the role of CX3CL1 signaling is complex and multifaceted, and it was an oversight not to have cited the studies listed in the comment. The manuscript by the Limatola group (Cipriani et al., 2011) reinforces what many scientists have already speculated about the complex role of CX3CR1/CX3CL1 signaling in disease. Indeed, the authors showed that wild-type mice and CX3CL1 knock-out mice with is...
We agree with the comment that the role of CX3CL1 signaling is complex and multifaceted, and it was an oversight not to have cited the studies listed in the comment. The manuscript by the Limatola group (Cipriani et al., 2011) reinforces what many scientists have already speculated about the complex role of CX3CR1/CX3CL1 signaling in disease. Indeed, the authors showed that wild-type mice and CX3CL1 knock-out mice with ischemia respond in opposite ways to CX3CL1 signaling: the chemokine protects wild-type mice, but harms knock-outs.
In our study, we showed that loss of CX3CL1/CX3CR1 signaling disrupted synaptic plasticity in male CX3CR1 -/- mice, and this effect was mediated by pro-inflammatory cytokines, because IL1ra improved synaptic plasticity and cognitive function. The Limatola group has previously shown that mice lacking CX3CR1 have improved LTP, a finding opposite to our findings. One possible explanation for this discrepancy is that at least some studies performed by this group (Maggi et al., 2009; Maggi et al., 2011) were conducted in female mice and our studies were performed in male mice. If CX3CR1/CX3CL1 signaling is gender-dependent this is very interesting and deserves to be investigated further. None of the studies so far, including ours, have investigated gender differences or the role of sex hormones on the function of CX3CL1/CX3CR1 signaling.
Reference
Cipriani R, Villa P, Chece G, Lauro C, Paladini A, Micotti E, Perego C, De Simoni MG, Fredholm BB, Eusebi F, Limatola C. CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. J Neurosci. 2011 Nov 9;31(45):16327-35
Maggi L, Trettel F, Scianni M, Bertollini C, Eusebi F, Fredholm BB, Limatola C (2009) LTP impairment by fractalkine/CX3CL1 in mouse hippocampus is mediated through the activity of adenosine receptor type 3 (A3R). J Neuroimmunol 215: 36-42
Maggi L, Scianni M, Branchi I, D'Andrea I, Lauro C, Limatola C (2011) CX(3)CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Front Cell Neurosci 5:22
This article by Gemma and coworkers contains data that in part conflict with our recently published papers on the effects of CX3CL1/CX3CR1 signaling in hippocampal physiology. In particular, the observation of Gemma that CX3CR1 deficiency in CX3CR1-/- but also in CX3CR1+/- mice results in a complete absence of LTP in the hippocampus (induced by two trains of 1s, 100 Hz) is in sharp contrast with our data that in CX3CR1GFP...
This article by Gemma and coworkers contains data that in part conflict with our recently published papers on the effects of CX3CL1/CX3CR1 signaling in hippocampal physiology. In particular, the observation of Gemma that CX3CR1 deficiency in CX3CR1-/- but also in CX3CR1+/- mice results in a complete absence of LTP in the hippocampus (induced by two trains of 1s, 100 Hz) is in sharp contrast with our data that in CX3CR1GFP/GFP knock-in mice two different protocols of LTP induction induced different results. In fact, when LTP was induced by applying 4 trains series of 100 Hz (1 s) spaced 3 s apart, no differences were observed between WT and CX3CR1 deficient mice (Maggi et al., 2009), while with a weak stimulation (LTP induced by 1 train at 100 Hz, 1 s) CX3CR1-deficient mice had a more sustained LTP (Maggi et al., 2011). To cite only papers where CX3CR1/CX3CL1 deficient signaling and hippocampal plasticity is considered, Paolicelli et al. (2011) performed experiments on CX3CR1-/- mice to investigate, among the other effects, developmental- dependent alteration in hippocampal synaptic plasticity, reporting no effect on adult mice and LTD potentiation in very young mice. In several other papers the effects of CX3CL1/CX3CR1 signaling on hippocampal physiology was investigated (Limatola et al., 2005; Bertollini et al., 2006; Ragozzino et al., 2006; Lauro et al., 2008; Piccinin et al., 2010) but none of these papers were considered for discussion in Gemma's manuscript. In addition, in one more recent publication (Maggi et al., 2011) the effect of CX3CR1 deficiency on mice behavior in the Morris water maze test was analyzed (and the same experiment is shown in Gemma's manuscript), but this paper was published only at the end of October, probably too late to be considered by these authors.
References
Bertollini C., Ragozzino D. Gross C. Limatola C. Eusebi F. Fractalkine/CX3CL1 depresses central synaptic transmission in mouse hippocampal slices. (2006) Neuropharmacology 51:816-21.
Lauro C., Di Angelantonio S., Cipriani R., Sobrero F., Antonilli L., Brusadin V., Ragazzino D. & Limatola C. Activity of adenosine receptors type 1 is required for CX3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons. (2008) J Immunol 180:7590-7596.
Limatola C., Lauro C., Catalano M., Ciotti MT., Bertollini C., Di Angelantonio S., Ragozzino D., and Eusebi F. Chemokine CX3CL1 protects rat hippocampal neurons against glutamate-mediated excitotoxicity (2005) J Neuroimmunol 166, 19-28.
Maggi L, Scianni M, Branchi I, D'Andrea I, Lauro C, Limatola C. CX3CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Front Cell Neurosci (2011), 5-22: 1-9.
Maggi L, Trettel F, Scianni M, Bertollini C, Eusebi F, Fredholm BB & Limatola C LTP impairment by fractalkine/CX3CL1 in mouse hippocampus is mediated through the activity of adenosine receptor type 3 (A3R). (2009) J Neuroimmunol. 215:36-42.
Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT. Synaptic pruning by microglia is necessary for normal brain development. (2011) Science 333:1456-8.
Piccinin S, Di Angelantonio S, Piccioni A, Volpini R, Cristalli G, Fredholm BB, Limatola C, Eusebi F, Ragozzino D. CX3CL1-induced modulation at CA1 synapses reveals multiple mechanisms of EPSC modulation involving AR subtypes. (2010) J Neuroimmunol, 224:85-92.
Ragozzino D, Di Angelantonio S, Trettel F, Bertollini C, Maggi L, Gross C, Charo IF, Limatola C and Eusebi F. Chemokine fractalkine/CX3CL1 negatively modulates active glutamatergic synapses in rat hippocampal neurons. (2006) J Neurosci 26, 10488-10498.
None declared