The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain

Abstract

Interleukin (IL)-22 is a potent mediator of inflammatory responses. The IL-22 receptor consists of the IL-22Rα and IL-10Rβ subunits. Previous studies have shown that IL-22Rα expression is restricted to non-hematopoietic cells in the skin, pancreas, intestine, liver, lung, and kidney. Although IL-22 is involved in the development of inflammatory responses, there have been no reports of its role in brain inflammation. Here, we used RT-PCR, Western blotting, flow cytometry, immunohistochemical, and microarray analyses to examine the role of IL-22 and expression of IL-22Rα in the brain, using the microglial cell line, hippocampal neuronal cell line, and inflamed mouse brain tissue. Treatment of BV2 and HT22 cells with recombinant IL-22 increased the expression levels of the pro-inflammatory cytokines IL-6 and TNF-α, as well as cyclooxygenase (COX)-2 and prostaglandin E2. We also found that the JNK and STAT3 signaling pathways play an important role in IL-22-mediated increases in inflammatory mediators. Microarray analyses revealed upregulated expression of inflammation-related genes in IL-22-treated HT22 cells. Finally, we found that IL-22Rα is spontaneously expressed in the brain and is upregulated in inflamed mouse brain. Overall, our results demonstrate that interaction of IL-22 with IL-22Rα plays a role in the development of inflammatory responses in the brain.

In schizophrenia, the effects of the IL-6/IL-23/Th17 axis on health-related quality of life and disabilities are partly mediated by generalized cognitive decline and the symptomatome

“…As previously discussed, IL-23 and IL-6 are important inducers of proliferation and survival of the pathogenic Th-17 phenotype as well as IL-17 production (Al-Hakeim et al, 2022). Increased IL-6, IL-23, and Th-17-related cytokines have a variety of neuroimmunotoxic effects, including activating autoimmune responses, maintaining persistent peripheral inflammation and neuroinflammation, lowering hippocampal neurogenesis, microglial activation, CNS tissue damage, and induction of the JAK-STAT and MAP-kinase pathways (Nitsch et al, 2019; Tahmasebinia and Pourgholaminejad, 2017; Liu et al, 2014; Langrish et al, 2005; Leavy et al, 2014; Lee et al, 2022; Liang et al, 2010). In schizophrenia, such mechanisms have been linked to abnormalities in neuroplasticity, synapse assembly, synapse structure, axonal branching and axogenesis, excitatory synaptic functioning, and pre- and post-synaptic neural connections (Maes et al, 2021a).…”

The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis

“…Furthermore, following stroke, IL-21 and its receptor are expressed in the CNS via brain infiltrating CD4+ T cells and CNS IL-21 strongly contributes to CNS tissue damage (117). IL-22 is expressed in the brain in physiological conditions, and is upregulated during neuroinflammatory conditions (118, 119). While this cytokine may have protective effects (119, 120) and induces an acute phase response (121) it may also display more detrimental inflammatory effects (99).…”

“…While this cytokine may have protective effects (119, 120) and induces an acute phase response (121) it may also display more detrimental inflammatory effects (99). Most importantly, during inflammatory responses IL-22 is upregulated in the brain and may increase the production of TNF-α, IL-6, and prostaglandins and induce STAT3, MAP-kinase, and JAK-STAT pathways (118), which all play a role in schizophrenia (118, 122).…”

Interleukin 22 and its association with neurodegenerative disease activity

“…Although microglia have protective activity, hyperactivated microglia release high levels of inflammatory cytokines such as IL-6, IL-1β, and TNF-α, leading to neuronal death and chronic inflammation, which is the degenerative main cause of encephalopathy ( Cervellati et al, 2020 ; Wu et al, 2021 ). In addition, the expression level of COX-2 is quickly upregulated in inflammatory circumstances, and IL-22-treated BV2 and HT22 cells revealed a considerable rise in COX-2 mRNA expression ( Lee et al, 2022 ), and PGE2 synthesis in both cells enhanced ( Nikoopour et al, 2015 ). This shows that by activating COX-2, IL-22 may boost PGE2 synthesis.…”

“…This shows that by activating COX-2, IL-22 may boost PGE2 synthesis. Using the Affymetrix GeneChip Mouse Gene 2.0 ST array, Dahae Lee et al (2022) evaluated the expression levels of inflammatory cytokine genes in HT22 cells, following IL-22 administration and discovered that roughly one-third of inflammatory cytokines were upregulated.…”