Delivery of IL-35 by Lactococcus lactis Ameliorates Collagen-Induced Arthritis in Mice.

Massimo Maddaloni,Carol Hoffman,Irina Kochetkova,David W Pascual

doi:10.3389/fimmu.2018.02691

Massimo Maddaloni, Carol Hoffman + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2018.02691

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Abstract

IL-35, a relatively newly discovered cytokine belonging to the larger IL-12 family, shows unique anti-inflammatory properties, believed to be associated with dedicated receptors and signaling pathways. IL-35 plays a pivotal role in the development and the function of both regulatory B (Bregs) and T cells (Tregs). In order to further its therapeutic potential, a dairy Lactococcus lactis strain was engineered to express murine IL-35 (LL-IL35), and this recombinant strain was applied to suppress collagen-induced arthritis (CIA). Oral administration of LL-IL35 effectively reduced the incidence and disease severity of CIA. When administered therapeutically, LL-IL35 abruptly halted CIA progression with no increase in disease severity by reducing neutrophil influx into the joints. LL-IL35 treatment reduced IFN-γ and IL-17 3.7- and 8.5-fold, respectively, and increased IL-10 production compared to diseased mice. Foxp3+ and Foxp3− CD39+ CD4+ T cells were previously shown to be the Tregs responsible for conferring protection against CIA. Inquiry into their induction revealed that both CCR6+ and CCR6− Foxp3+or− CD39+ CD4+ T cells act as the source of the IL-10 induced by LL-IL35. Thus, this study demonstrates the feasibility and benefits of engineered probiotics for treating autoimmune diseases.

Highlights

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease that affects about 0.24% of the worldwide population, and roughly 1% of the general population in Western countries
To address the void for such tolerance induction, we queried whether a probiotic lactic acid bacteria (LAB) engineered to express the potent anti-inflammatory cytokine, IL-35 (Figure 1A), would diminish arthritis
Expression of IL-35 by LL-IL35 was detected by Western blot analysis using a rabbit polyclonal serum against an MBPIL-35 fusion protein [produced in-house; [61]]

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease that affects about 0.24% of the worldwide population, and roughly 1% of the general population in Western countries. In agreement with these clinical findings, the LL-IL35-treated mice had markedly reduced Ly-6G+ CD11b+ cells (neutrophils) infiltrating the joints (Figure 2A) representing a 7- and 5-fold reduction compared to SD sequence present in the vector. IL-17 levels were significantly less (p < 0.001) by 3.7- and 8.5-fold for LL vector and LL-IL35-treated groups, respectively, relative to PBS-dosed mice (Figure 3B).

Results

Conclusion