IL-25 exacerbates autoimmune aortitis in IL-1 receptor antagonist-deficient mice

Takamichi Yoshizaki,Aya Nambu,Takafumi Numata,Atsushi Yamaguchi,Naoyuki Kimura,Satoshi Itoh,Sachiko Yamaguchi,Katsuko Sudo,Susumu Nakae,Ko Okumura,Hajime Suto

doi:10.1038/s41598-019-53633-0

Abstract

IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses. Mice deficient in IL-1 receptor antagonist (Il1rn−/− mice) have excessive IL-1 signaling, resulting in spontaneous development of IL-1–, TNF– and IL-17A–dependent aortitis. We found that expression of II25 mRNA was increased in the aortae of Il1rn−/− mice, suggesting that IL-25 may suppress development of IL-1–, TNF– and IL-17A–dependent aortitis in Il1rn−/− mice by inhibiting type 3-mediated immune responses. However, we unexpectedly found that Il25−/−Il1rn−/− mice showed attenuated development of aortitis, accompanied by reduced accumulation of inflammatory cells such as dendritic cells, macrophages and neutrophils and reduced mRNA expression of Il17a and Tnfa—but not Il4 or Il13—in local lesions compared with Il1rn−/− mice. Tissue–, but not immune cell–, derived IL-25 was crucial for development of aortitis. IL-25 enhanced IL-1β and TNF production by IL-25 receptor–expressing dendritic cells and macrophages, respectively, at inflammatory sites of aortae of Il1rn−/− mice, contributing to exacerbation of development of IL-1–, TNF– and IL-17A–dependent aortitis in those mice. Our findings suggest that neutralization of IL-25 may be a potential therapeutic target for aortitis.

Highlights

IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses
Mice deficient in IL-1 receptor antagonist (Il1rn−/− mice) had excessive IL-1 signaling, resulting in spontaneous development of aortitis accompanied by infiltration of predominantly lymphocytes, which contributed to destruction of the elastic laminae with fibrosis, resembling large-vessel vasculitides (LVV) such as Takayasu arteritis (TAK) and GCA20,21
We found that CD11c+ dendritic cells (DCs), Gr1+ neutrophils, and GL3+ γδT cells—but not CD4+ T cells, CD8+ T cells or Mac2+ macrophages—were IL-1Ra–producing EGFP+ cells in the lesions of aortitis (Fig. 3a, and data not shown)

Summary

Introduction

IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses. We found that expression of II25 mRNA was increased in the aortae of Il1rn−/− mice, suggesting that IL-25 may suppress development of IL-1–, TNF– and IL-17A–dependent aortitis in Il1rn−/− mice by inhibiting type 3-mediated immune responses. Mice deficient in IL-1 receptor antagonist (Il1rn−/− mice) had excessive IL-1 signaling, resulting in spontaneous development of aortitis accompanied by infiltration of predominantly lymphocytes, which contributed to destruction of the elastic laminae with fibrosis, resembling LVV such as TAK and GCA20,21. The spontaneous development of aortitis in those Il1rn−/− mice was dependent on T cells, whereas it was suppressed by deficiency of TNF-α or IL-17A, but not IL-622,23 Based on those findings in Il1rn−/− mice, a therapeutic trial www.nature.com/scientificreports of Anakinra (recombinant human IL-1RN) in GCA patients found that its blockade of IL-1 activity was effective for treatment of the disease[24]. We demonstrate that IL-25 plays a facilitative role in the development of IL-1–, TNF– and IL-17A–mediated aortitis in Il1rn−/− mice

Methods

Results

Conclusion