IL-37 expression reduces acute and chronic neuroinflammation and rescues cognitive impairment in an Alzheimer’s disease mouse model
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Evaluation Summary:
This study will be of interest to scientists studying neuroinflammation and searching for potential therapeutic targets. The findings here have revealed the effects of an anti-inflammatory cytokine, human IL-37 (hIL-37), in the central nervous system of mice. The data support the conclusions within the current mouse models. Since hIL-37 is not naturally expressed in mice, more evidence related to human cells or tissues would strengthen the physiological significance.
This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.
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Abstract
The anti-inflammatory cytokine interleukin-37 (IL-37) belongs to the IL-1 family but is not expressed in mice. We used a human IL-37 (hIL-37tg) expressing mouse, which has been subjected to various models of local and systemic inflammation as well as immunological challenges. Previous studies reveal an immunomodulatory role of IL-37, which can be characterized as an important suppressor of innate immunity. Here, we examined the functions of IL-37 in the central nervous system and explored the effects of IL-37 on neuronal architecture and function, microglial phenotype, cytokine production and behavior after inflammatory challenge by intraperitoneal LPS-injection. In wild-type mice, decreased spine density, activated microglial phenotype and impaired long-term potentiation (LTP) were observed after LPS injection, whereas hIL-37tg mice showed no impairment. In addition, we crossed the hIL-37tg mouse with an animal model of Alzheimer’s disease (APP/PS1) to investigate the anti-inflammatory properties of IL-37 under chronic neuroinflammatory conditions. Our results show that expression of IL-37 is able to limit inflammation in the brain after acute inflammatory events and prevent loss of cognitive abilities in a mouse model of AD.
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Evaluation Summary:
This study will be of interest to scientists studying neuroinflammation and searching for potential therapeutic targets. The findings here have revealed the effects of an anti-inflammatory cytokine, human IL-37 (hIL-37), in the central nervous system of mice. The data support the conclusions within the current mouse models. Since hIL-37 is not naturally expressed in mice, more evidence related to human cells or tissues would strengthen the physiological significance.
This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.
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Reviewer #1 (Public Review):
In this study, Lonnemann et al. investigated the anti-inflammatory effects of hIL-37 in acute and chronic neuroinflammatory mouse models, using both in vivo and in vitro assays. The data provided support for the anti-inflammatory functions of IL-37 on microglial activation and cognitive functions.
As a cytokine that is not naturally expressed in mice, the introduction of the physiological significance of IL-37 in human beings and the necessity of this research in the background will be insightful.
A comprehensive analysis for how hIL-37 may affect metabolite content would strengthen the conclusion.
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Reviewer #2 (Public Review):
The authors have asked the question of how the 'neuroprotective' IL-37 signaling pathway modulates pro-inflammatory microglial activation, and thereby impacts neuronal health, synaptic plasticity in LPS-dependent neuroinflammation and amyloid metabolism and pathways affecting cognitive function in the APPPS1 mouse model of Alzheimer's disease.
The use of in-vitro assays using primary, murine microglia from transgenic IL-37 tg/wt and IL-37 tg/tg mice for metabolic profiling following LPS-stimulated, pro-inflammatory activation, along with the generation and use of APPPS1-IL37tg/tg mouse model to demonstrate the anti-inflammatory / neuroprotective effect of IL-37 signaling are major strengths of this work.
The authors do an excellent job in designing experiments to ask and test logical questions that arise as …
Reviewer #2 (Public Review):
The authors have asked the question of how the 'neuroprotective' IL-37 signaling pathway modulates pro-inflammatory microglial activation, and thereby impacts neuronal health, synaptic plasticity in LPS-dependent neuroinflammation and amyloid metabolism and pathways affecting cognitive function in the APPPS1 mouse model of Alzheimer's disease.
The use of in-vitro assays using primary, murine microglia from transgenic IL-37 tg/wt and IL-37 tg/tg mice for metabolic profiling following LPS-stimulated, pro-inflammatory activation, along with the generation and use of APPPS1-IL37tg/tg mouse model to demonstrate the anti-inflammatory / neuroprotective effect of IL-37 signaling are major strengths of this work.
The authors do an excellent job in designing experiments to ask and test logical questions that arise as the data is developed. However, certain aspects of the data should be carefully interpreted, as the manuscript does not directly test the interpretations made.
While the data presented raises some interesting hypotheses, the manuscript is limited in discussing their findings in the context of the larger-picture of distinct sub-clusters of microglial activation, microglial metabolic reprogramming/dysfunction and neurodegeneration in AD.
Lastly, due to already existing data that suggests that IL-37 may play a limited role in AD pathology, this study may be of potential but limited interest to the field of AD-related neurodegeneration.
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Reviewer #3 (Public Review):
In this manuscript, the authors demonstrated that acute and chronic neuroinflammation was attenuated in hIL-37 transgenic mice, suggesting that recombinant IL-37 might be a therapeutic option for neuroinflammation. However, additional mechanistic insights may be required for better elucidating IL-37's effects in neuroinflammation.
1. In vitro phenotypes in Fig.1 were not closely connected with the following in vivo neuroinflammation phenotypes. Although three different neuroinflammation models were used, the detailed mechanisms for how IL-37 reduced neuroinflammation were not well addressed.
1.1 Fig. 3 and Fig. 5 showed reduced pro-inflammatory cytokine production in brain lysates. However, glial cells other than microglia, such as astrocytes and infiltrating leukocytes could be sources of inflammatory …
Reviewer #3 (Public Review):
In this manuscript, the authors demonstrated that acute and chronic neuroinflammation was attenuated in hIL-37 transgenic mice, suggesting that recombinant IL-37 might be a therapeutic option for neuroinflammation. However, additional mechanistic insights may be required for better elucidating IL-37's effects in neuroinflammation.
1. In vitro phenotypes in Fig.1 were not closely connected with the following in vivo neuroinflammation phenotypes. Although three different neuroinflammation models were used, the detailed mechanisms for how IL-37 reduced neuroinflammation were not well addressed.
1.1 Fig. 3 and Fig. 5 showed reduced pro-inflammatory cytokine production in brain lysates. However, glial cells other than microglia, such as astrocytes and infiltrating leukocytes could be sources of inflammatory cytokines. There was no evidence supporting that reduced cytokine levels were intrinsic to microglia as modelled in the in vitro system. Thus, in vitro and in vivo phenotypes appeared somewhat disconnected.
1.2 In Fig. 5, IL-1β-induced neuroinflammation model was used to demonstrate the beneficial effects of IL-37 on cognition and synaptic function. Could injection of recombinant IL-37 display similar effects for LPS challenge model in Fig. 3 and Fig. 4?
1.3 Reduced IL-37-mediated neuroinflammation was shown in both chronic and acute models in the manuscript. Did microglia or other cells play a major role in those models? The detailed mechanisms regarding cell type contribution were largely missing in the manuscript.
2. Fig. 2 showed differential metabolomic profiling of microglial cells between WT and IL-37tg mice. However, there were no further evidence demonstrating that the metabolic function of microglial cells was indeed altered by IL-37 expression. It would be better to show the results of seahorse or other metabolic functional assays.
3. The models for acute neuroinflammation including LPS and IL-1β challenge were systematic inflammation. It might be reasonable to propose that reduced neuroinflammation was secondary effect to reduced inflammation response in periphery. In addition, in Fig. 3, would injection of LPS twice induce tolerance responses?
4. In Fig. 3 and Fig. 6, CD68 was used as activation marker for microglia. However, CD68 expression by itself is not enough to define microglia to be in the activation state. The phenotypic changes of microglial cells would also depend on specific models used. Additional experimental evidence is needed for defining the reduced activation status of microglia in IL-37tg mice.
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