The Role of Mast Cells in Stroke
Round 1
Reviewer 1 Report
With interest, I read the manuscript cells-487041. I believe that areas of the scientific overalp are always very interesting and good reviews summarizing the state of the art are from time to time necessary.
Specific comments:
1. This review would benefit much from figures illustrating the mechanisms of MCs involvement in the pathogenesis of stroke. One figure should illustrate the ischemic stroke, while the other hemorrhagic form of the disease. If childhood and adulthood forms of ischemic stroke cannot be put together, then two separate figures should be created. The same for ICH and SAH.
2. Line 41. Please, refer to the review PMID: 24315352 for the involvement of MC in the pathogenesis of other CV disorders, such as MI. By this occasion, please, refer to the existence of the overlap between allergic and CV mechanisms/disorders.
3. In continuation of it, one of the forms of MI with especially important role of MC is so-called Kounis syndrome. No surprisingly, MCS stabilizers might be useful also there (PMID: 26966931). Please, discuss this parallel.
4. Lines 131-139. This part addresses experimental treatment. Should it not be moved to section “4. Pharmacological interventions targeting MCs in stroke”? Or it is used only here to discuss the mechanisms?
5. Lines 265-266. Are not those two drugs targeting IgE-dependent activation of MCs? Would they be applicable in stroke then?
6. In continuation, are there any speculations about the relationships between IgE-dependent allergies and stroke?
7. What I miss in this review is genetics and epigenetics. A short section on those would be welcome.
8. Table 2 looks graphically better than Table 1. Either the spaces between the part of the text are too large in Table 1 or it would look better if made horizontal.
Author Response
Response to Reviewer 2 (please note that changes and revisions throughout the manuscript text were highlighted in yellow)
Comments and Suggestions for Authors
With interest, I read the manuscript cells-487041. I believe that areas of the scientific overalp are always very interesting and good reviews summarizing the state of the art are from time to time necessary.
Specific comments:
1. This review would benefit much from figures illustrating the mechanisms of MCs involvement in the pathogenesis of stroke. One figure should illustrate the ischemic stroke, while the other hemorrhagic form of the disease. If childhood and adulthood forms of ischemic stroke cannot be put together, then two separate figures should be created. The same for ICH and SAH.
Since the mechanisms of MCs involvement in the pathogenesis of stroke are similar in ischemic stroke and ICH, we included one single figure to illustrate the two stroke subtypes (Figure 1). The mechanisms depicted in figure 1 are valid for both adult and immature brain. We included a second figure (Figure 2) to describe the role of MCs in SAH pathogenesis.
2. Line 41. Please, refer to the review PMID: 24315352 for the involvement of MC in the pathogenesis of other CV disorders, such as MI. By this occasion, please, refer to the existence of the overlap between allergic and CV mechanisms/disorders.
and
3. In continuation of it, one of the forms of MI with especially important role of MC is so-called Kounis syndrome. No surprisingly, MCS stabilizers might be useful also there (PMID: 26966931). Please, discuss this parallel.
We discussed the overlap between allergic and CV disorders and the Kounis syndrome at page 2, lines 47-50. The references suggested by the reviewer and another one on Kounis syndrome have been added to the text (references 25-27).
4. Lines 131-139. This part addresses experimental treatment. Should it not be moved to section “4. Pharmacological interventions targeting MCs in stroke”? Or it is used only here to discuss the mechanisms?
That part was placed in the section “MCs and stroke” only to discuss the role of MCs in the hemorrhagic conversion promoted by rtPA treatment. We added a sentence to make it clearer (lines 173-175).
5. Lines 265-266. Are not those two drugs targeting IgE-dependent activation of MCs? Would they be applicable in stroke then?
Resveratrol and polydatin are able to target IgE-dependent activation of MCs as reported in the references we cited (references 196-200). Therefore, their beneficial effects in stroke models could be partially mediated by their modulatory action on MCs. We added a sentence to explain this correlation (page 11, lines 338-342).
6. In continuation, are there any speculations about the relationships between IgE-dependent allergies and stroke?
We added a short discussion about the relationship between IgE and stroke at page 2, lines 50-54. Proper papers have been cited (references 28-30).
7. What I miss in this review is genetics and epigenetics. A short section on those would be welcome.
Thanks for the suggestion. We added a novel section on trascriptional and epigenetic regulation of MCs response (section 3, pages 2-3, lines 84-102). Relevant papers have been cited and discussed (references 37-51).
8. Table 2 looks graphically better than Table 1. Either the spaces between the part of the text are too large in Table 1 or it would look better if made horizontal.
We formatted Table 1 in order to make it more similar to Table 2.
Reviewer 2 Report
Parrella et colleagues provide a reasonable overview of the role of mast cells in stroke, focusing on experimental stroke models and potential drug targeting MCs. While the current state of the field in term of preclinical data is comprehensively analysed, the actual knowledge of MC contribution to human stroke should be better highlighted (also if available data are limited). Similarly, the conclusion section can be expanded indicating the best avenues for future research (for example, can they better characterise specific MC mediators involved in the pathogenesis of stroke leading to a more targeted pharmacological treatment rather than the use of a general approach for targeting MC?)
Minor considerations: past and more recent experimental studies are correctly presented and discussed, however some clinical data should be rather provided with more recent references (i.e. 31, 37, 38, 39, 40, 51, 65, 69). In addition, there are a few papers missing that are worthy to be discussed (i.e. Arac et al., Am J Pathol 2014 on the role of meningeal MC on stroke; McKittrick et al., J Cereb Blood Flow Metab. 2015 on MC role in a model of focal cerebral ischemia; Kuwabara et al., Neurosurgery 2017 on the potential of mesenchymal stem cells to stabilize MC degranulation). Finally, is reference [44] appropriate? I can’t find any reference to MC in the suggested review. The last sentence of the conclusions should be clarified.
Author Response
Response to Reviewer 3 (please note that changes and revisions throughout the manuscript text were highlighted in green).
Comments and Suggestions for Authors
Parrella et colleagues provide a reasonable overview of the role of mast cells in stroke, focusing on experimental stroke models and potential drug targeting MCs.
While the current state of the field in term of preclinical data is comprehensively analysed, the actual knowledge of MC contribution to human stroke should be better highlighted (also if available data are limited).
As pointed out by the reviewer, available data on the contributions of MCs in human stroke are limited. However, we cited and discussed the studies investigating the presence of MCs in stroke patients: Arsene et al. 2011, on the analysis of the brain of patients deceased after suffering an ischemic stroke (reference 95: page 4, lines 166-169; page 9, table 1; page 14, line 390); Harsan et al. J. Neuroinflammation 2012, Harsan et al. Arterioscler Thromb Vasc Biol. 2012, Ollikainen et al. 2014, on the analysis of aneurysm tissues of cerebral aneurysm patients that underwent microsurgical clipping (references 121-123: page 6, lines 224-226; page 9, table 1; page 14, line 390); Faleiro et al. 1981, on the analysis of cerebral arteries of patients who died after subarachnoid hemorrhage (reference 125: page 6, line 233-234; page 9, table 1; page 14, line 390). Moreover, we included a new part in the conclusion section discussing the need of studies on stroke patients (page 14, lines 390-396).
Similarly, the conclusion section can be expanded indicating the best avenues for future research (for example, can they better characterize specific MC mediators involved in the pathogenesis of stroke leading to a more targeted pharmacological treatment rather than the use of a general approach for targeting MC?)
As requested by the reviewer, we expanded the conclusion section indicating possible novel approaches in clinical targeting of MCs functions (pages 13-14, lines 373-389).
Minor considerations: past and more recent experimental studies are correctly presented and discussed, however some clinical data should be rather provided with more recent references (i.e. 31, 37, 38, 39, 40, 51, 65, 69).
As suggested by the reviewer, we added more recent clinical data. In particular we included the following references: Lehman and Rivkin 2014 (page 3, line 109, reference 53); Krishnamurthi et al. 2018 (page 3, line 113, reference 61); Kirton and deVeber 2013, McNally and Soul 2019 (page 3, line 119, references 64, 65); Chamorro et al. 2016 ( page 3, line 137, reference 79); Moretti et al. 2015 (page 4, line 171, reference 97); Sansing 2016 (page 4, line 183, reference 103).
In addition, there are a few papers missing that are worthy to be discussed (i.e. Arac et al., Am J Pathol 2014 on the role of meningeal MC on stroke; McKittrick et al., J Cereb Blood Flow Metab. 2015 on MC role in a model of focal cerebral ischemia; Kuwabara et al., Neurosurgery 2017 on the potential of mesenchymal stem cells to stabilize MC degranulation).
Thaks for the advice. We included and discussed the papers suggested by the reviewer: Arac et al., Am J Pathol 2014 (page 4, lines 163-166 and page 8, table 1, reference 94); McKittrick et al., J Cereb Blood Flow Metab. 2015 (page 4, lines 154-158; page 8, table 1; page 12, table 2; reference 91); Kuwabara et al., Neurosurgery 2017 (page 11, lines 314-319 and page 13, table 2, reference 176).
Finally, is reference [44] appropriate? I can’t find any reference to MC in the suggested review.
We replaced the reference 44 with the following papers linking perinatal brain injury and MCs: Lai et al., Brain Behav Immun. 2017; Hagberg et al., Nat Rev Neurol. 2015 (page 3, line 122, references 69 and 70).
The last sentence of the conclusions should be clarified.
We modified the sentence (page 14, lines 395-396).
Round 2
Reviewer 1 Report
Thank you for addressing my comments.
Author Response
Thanks to you.
Reviewer 2 Report
The authors have addressed all my previous concerns and the manuscript is greatly improved in the revised version, including two new elucidative figures.
As a final personal consideration to both the authors and the editor(s), I still had the feeling that in term of structure, and particularly in some points (i.e. the section: Intervention targeting MCs in stroke), this manuscript mirrors too closely a recent work by Ocak et colleagues (Brain Injury, 2018; Ref. 24 in the current version of the paper). I can understand that the organization of the framework is limited by the narrow amount of information, but a different presentation of the topic would have improved its novelty and interest for the scientific community. Can the authors comment on that?
Author Response
We are aware that our review shares similarities with the work by Ocak et colleagues and also other reviews on the role of MCs in neurodegenerative diseases (see for example the papers cited in our manuscript: Nelissen et al. 2013, Siver and Curley 2013, Dong et al. 2014, Hendriksen et al. 2017, Traina 2017).
About the section "Intervention targeting MCs in stroke", please note that our abstract describing the purpose to discuss the role of MCs modulators in stroke treatment ("...Further, we discuss the role of MCs as potential targets for the treatment of stroke and the compounds potentially active as MCs modulators.") was sent to Cells editor on October 8th 2018, while the work by Ocak et al. was accepted on November 19th 2018.
When we found the paper by Ocak, we payed attention to make that section different from the review just published. Specifically, besides the pharmacological modulators cited by Ocak and colleagues, we discussed additional interventions, including treatment with carnosine, emedastine, tranilast, mesenchymal stem cells, scopoletin, resveratrol and polydatin. Moreover, we added table 2 to summarize the described interventions.
However, since the title of our section (“Interventions targeting MCs in stroke”) could appear too similar to the corresponding section in Ocak paper ("Pharmacological strategies targeting at mast cells"), we changed it to “MCs modulation: a promising strategy in stroke treatment” (page 10, line 254). Similarly, we changed the title of Table 2 (“Drugs targeting MCs in stroke models”) to “Therapeutic modulation of MCs in stroke models” (page 11, line 351).
