Cell-type specific IL-1 response in autoimmune neuroinflammation and its regulation by the decoy receptor IL-1R2

• Applicant: Dr. Ilgiz Mufazalov, Ph.D.
• Subject Area: Immunology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457023217

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) with currently no definitive cure. Interleukin-1 (IL-1) is critically involved in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Pathogenic effects of IL-1 are mediated through boosting IL-17–producing CD4+ T-helper (Th17) cells and repressing Foxp3+ regulatory T (Treg) cells. However, the mechanisms by which IL-1 regulates the terminal differentiation of these T cell populations, and how myeloid cells, including inflammation-predominated cell subsets such as neutrophils and macrophages, interact with pathogenic and tolerogenic T cells remains elusive. Signaling of IL-1 is strictly mediated via the IL-1 receptor type 1 (IL-1R1). In contrast, the decoy IL-1 receptor type 2 (IL-1R2), which lacks a signaling domain, dampens IL-1 responses in cis when expressed on IL-1 responding cells and in a paracrine manner upon shedding.The goal of our study is to reveal the mechanisms through which IL-1 facilitates the development of CNS-directed autoimmunity. First, we will study how IL-1 signaling affects Th17 and Treg cells. To this end, we will use a unique set of transgenic mice to selectively delete IL-1R1 or IL-1R2 from Th17 and Treg cells and follow their development and function in EAE. Next, to study how IL-1 and myeloid cell-derived IL-1R2 regulate autoimmunity, we will conditionally inactivate IL-1 receptors in macrophages and neutrophils. We will then study the susceptibility of these knockout mice to develop autoimmune responses. Finally, we plan to investigate the regulation of IL-1R2 expression. We previously observed that IL-1R2 deficiency, as well as, interferon-γ (IFNγ) neutralization allows EAE development even in the absence of pertussis toxin administration, an essential trigger of IL-1 production and EAE development in C57BL/6 mice. These data suggest a novel IFNγ–IL-1R2 regulatory axis and we plan to investigate how IFNγ signaling affects the function of IL-1R2 by using mice lacking the IFNγ receptor in myeloid cells. Furthermore, we will determine how IFNγ regulates the expression and shedding of IL-1R2 by analyzing the gene and protein expression profile of myeloid cells treated with IFNγ.In this innovative study we will induce EAE in mice with conditional inactivation (via IL-1R1 deficiency) or enhancement (via IL-1R2 deficiency) of IL-1 signaling in selected subsets of CD4+ T cells and myeloid cells. We will then analyze peripheral and CNS-infiltrated cells isolated from these conditional knockout mice at different EAE stages with a specific focus on Th17, Treg cells and neutrophils. We are confident that this study will provide a better understanding of the mechanisms by which IL-1 plays a crucial role in autoimmune neuroinflammation. We believe our results will help identify novel therapeutic targets for the treatment of patients with MS.

• DFG Programme: Research Grants