Temporal overexpression of IL‐22 and Reg3γ differentially impacts the severity of experimental autoimmune encephalomyelitis

Abstract

IL‐22 is an alpha‐helical cytokine which belongs to the IL‐10 family of cytokines. IL‐22 is produced by RORγt+ innate and adaptive lymphocytes, including ILC3, γδ T, iNKT, Th17 and Th22 cells and some granulocytes. IL‐22 receptor is expressed primarily by non‐haematopoietic cells. IL‐22 is critical for barrier immunity at the mucosal surfaces in the steady state and during infection. Although IL‐22 knockout mice were previously shown to develop experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), how temporal IL‐22 manipulation in adult mice would affect EAE course has not been studied previously. In this study, we overexpressed IL‐22 via hydrodynamic gene delivery or blocked it via neutralizing antibodies in C57BL/6 mice to explore the therapeutic impact of IL‐22 modulation on the EAE course. IL‐22 overexpression significantly decreased EAE scores and demyelination, and reduced infiltration of IFN‐γ+IL‐17A+Th17 cells into the central nervous system (CNS). The neutralization of IL‐22 did not alter the EAE pathology significantly. We show that IL‐22‐mediated protection is independent of Reg3γ, an epithelial cell‐derived antimicrobial peptide induced by IL‐22. Thus, overexpression of Reg3γ significantly exacerbated EAE scores, demyelination and infiltration of IFN‐γ+IL‐17A+ and IL‐17A+GM‐CSF+Th17 cells to CNS. We also show that Reg3γ may inhibit IL‐2‐mediated STAT5 signalling and impair expansion of Treg cells in vivo and in vitro. Finally, Reg3γ overexpression dramatically impacted intestinal microbiota during EAE. Our results provide novel insight into the role of IL‐22 and IL‐22‐induced antimicrobial peptide Reg3γ in the pathogenesis of CNS inflammation in a murine model of MS.

Immune cell‐intrinsic Ah receptor facilitates the expression of antimicrobial REG3G in the small intestine

“…Furthermore, REG3G expression has been linked to improved energy balance, glucose tolerance and attenuation of the severity of experimental autoimmune encephalomyelitis. 7,53 Importantly, broccoli-mediated increase in REG3G expression is induced in an AHR-dependent immune cell-centric manner. As such, diets rich in AHR ligands likely contribute to homeostatic control of the commensal microbiota and systemic health benefits.…”

“…Together, these data indicate that homeostatic maintenance of antimicrobial activity within the small intestine is dictated by AHR functionality within the immune system and that such functionality is influenced by dietary exposure to AHR ligands. Furthermore, REG3G expression has been linked to improved energy balance, glucose tolerance and attenuation of the severity of experimental autoimmune encephalomyelitis 7,53 . Importantly, broccoli‐mediated increase in REG3G expression is induced in an AHR‐dependent immune cell‐centric manner.…”

The Ability of AhR Ligands to Attenuate Delayed Type Hypersensitivity Reaction Is Associated With Alterations in the Gut Microbiota

“…IL-22 is a member of the IL-10 family produced by a variety of immune cells, including Th1, Th17 cells, and Th22 cells (52). IL22 acts primarily on nonhematopoietic cells that express IL22 receptor and provides barrier immunity at the mucosal surfaces (53). TCDD has been shown previously to induce IL22 in human CD4+ T cells in an AhR-dependent manner (54).…”

Neuroinflammation: Extinguishing a blaze of T cells

“…53 However, deletion of IL-22RA2 and overexpression of IL-22 reduce neuroinflammation in EAE mice. [116][117][118] These opposing roles during neuroinflammation could be attributed in part to the effect of IL-22 in improving the survival of astrocytes, also shown to express the IL-22R. 119…”

“…Also, compared to healthy controls, T cells expanded from the blood of MS patients express more IL‐22, which is thought to contribute to BBB disruption and thus promote transmigration of pathogenic CD4 T cells into the CNS 53 . However, deletion of IL‐22RA2 and overexpression of IL‐22 reduce neuroinflammation in EAE mice 116‐118 . These opposing roles during neuroinflammation could be attributed in part to the effect of IL‐22 in improving the survival of astrocytes, also shown to express the IL‐22R 119 …”