The Role of Pro-Inflammatory and Regulatory Signaling by IL-33 in the Brain and Liver: A Focused Systematic Review of Mouse and Human Data and Risk of Bias Assessment of the Literature

Abstract

Interleukin (IL)-33 is a member of the IL-1 family of proteins that have multiple roles in organ-specific inflammation. Many studies suggest diagnostic and therapeutic implications of this cytokine. Many studies have reported pro-inflammatory roles for IL-33 in innate immune responses involving the heart and lung. Recent studies also describe pro-inflammatory and regulatory roles for IL-33 in the pathogenesis of brain and liver disorders in addition to regulatory roles for this cytokine in the heart and lung. In this focused systematic review, we will review the literature regarding pro-inflammatory and regulatory effects of IL-33 in the brain and liver. We will also assess the potential risk of bias in the published literature in order to uncover gaps in the knowledge that will be useful for the scientific community. We utilized guidelines set by preferred reporting items for systemic reviews and meta-analyses. The electronic database was PubMed. Eligibility criteria included organ-specific inflammation in mice and humans, organ-specific inflammation in the central nervous and hepatic systems, and IL-33. Outcomes were pro-inflammatory or regulatory effects of IL-33. Risk of bias in individual studies and across studies was addressed by adapting the Cochrane Rob 2.0 tool. We discovered that a source of bias across the studies was a lack of randomization in human studies. Additionally, because the majority of studies were performed in mice, this could be perceived as a potential risk of bias. Regarding the central nervous system, roles for IL-33 in the development and maturation of neuronal circuits were reported; however, exact mechanisms by which this occurred were not elucidated. IL-33 was produced by astrocytes and endothelial cells while IL-33 receptors were expressed by microglia and astrocytes, demonstrating that these cells are first responders for IL-33; however, in the CNS, IL-33 seems to induce Th1 cytokines such as IL-1β and TNF-α chemokines such as RANTES, MCP-1, MIP-1α, and IP-10, as well as nitric oxide. In the liver, similar risks of bias were determined because of the lack of randomized controlled trials in humans and because the majority of studies were performed in mice. Interestingly, the strain of mouse utilized in the study seemed to affect the role of IL-33 in liver inflammation. Lastly, similar to the brain, IL-33 appeared to have ST2-independent regulatory functions in the liver. Our results reveal plausible gaps in what is known regarding IL-33 in the pathogenesis of brain and liver disorders. We highlight key studies in the lung and heart as examples of advancements that likely occurred because of countless basic and translational studies in this area. More research is needed in these areas in order to assess the diagnostic or therapeutic potential of IL-33 in these disorders.

Dual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation

“…Although many studies investigated the expression and roles of IL-33 in CNS diseases and resulting cognitive dysfunction since IL-33 was originally reported in 2005 [ 5 ], there is still no consensus regarding the distribution and the exact effect of IL-33 in the basal ganglia, cerebellum, cerebral cortex, hippocampus, and midbrain of humans [ 17 ]. IL-33 induced the phagocytosis and expression of pro-inflammatory cytokines in microglia in a dose-dependent manner [ 6 ].…”

“…IL-33 binds to its receptor on ST2expressing cells to induce the production of cytokines, chemokines, and potentially neurotoxic substances, such as IL-4, IL-13, IL-5, IL-6, IL-10, interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interferon-γ (IFNγ), nitric oxide (NO), and radical oxygen species (ROS) [6,15]. These mediators play pivotal roles in neuroinflammation or neuroprotection [16][17][18] and are significantly associated with the state of cognition [19][20][21][22].…”

Transcutaneous Electrical Nerve Stimulation (TENS) for Opioid‐Induced Constipation in Palliative Care: A Systematic Review and Network Meta‐Analysis

“…The Cochrane collaboration tool is commonly used to assess selection bias in meta-analyses of randomized controlled clinical trials [ 19 ]. It evaluates whether data allocation was random and whether any baseline differences between groups suggest issues with randomization [ 20 ]. This is precisely the objective of our study, and thus, we chose the Cochrane collaboration tool to evaluate the risk of bias.…”

Schizophrenia and Alarmins

“…IL-33, a member of the IL-1 family [47], has a three-dimensional structure with 12 β-strands arranged in a β-trefoil fold. IL-33 is mainly secreted by astrocytes and endothelial cells [48][49][50]. Whether oligodendrocytes [46,49] and neurons [51] can secrete remains controversial.…”