Photoreceptor Cells Constitutively Express IL-35 and Promote Ocular Immune Privilege

Abstract

Interleukin-27 is constitutively secreted by microglia in the retina or brain, and upregulation of IL-27 during neuroinflammation suppresses encephalomyelitis and autoimmune uveitis. However, while IL-35 is structurally and functionally similar to IL-27, the intrinsic roles of IL-35 in CNS tissues are unknown. Thus, we generated IL-35/YFP-knock-in reporter mice (p35-KI) and demonstrated that photoreceptor neurons constitutively secrete IL-35, which might protect the retina from persistent low-grade inflammation that can impair photoreceptor functions. Furthermore, the p35-KI mouse, which is hemizygous at the il12a locus, develops more severe uveitis because of reduced IL-35 expression. Interestingly, onset and exacerbation of uveitis in p35-KI mice caused by extravasation of proinflammatory Th1/Th17 lymphocytes into the retina were preceded by a dramatic decrease of IL-35, attributable to massive death of photoreceptor cells. Thus, while inflammation-induced death of photoreceptors and loss of protective effects of IL-35 exacerbated uveitis, our data also suggest that constitutive production of IL-35 in the retina might have housekeeping functions that promote sterilization immunity in the neuroretina and maintain ocular immune privilege.

Cytokines in Immune-mediated “Non-infectious” Uveitis

“…A considerable decrease of IL-35 (attributed to the massive death of photoreceptor cells) preceded the extravasation of proinflammatory Th1/Th17 lymphocytes into the retina, which eventually led to the onset and exacerbation of uveitis in p35-KI mice. Although the loss of IL-35 protective effects and inflammation-induced death of photoreceptors resulted in the exacerbation of uveitis, this study indicates that constitutive IL-35 secretion in the retina may be linked to functions that promote sterilisation immunity in the neuroretina, contributing to the maintenance of ocular immune privilege [86].…”

“…Yu et al [86] provided evidence that the cytokine IL-35 is involved in the pathogenesis of uveitis. They generated IL-35/YFPknock-in reporter mice (p35-KI) and showed that IL-35 is constitutively produced by photoreceptor neurons [86]. This might prevent impairment of photoreceptors following persistent lowgrade inflammation.…”

Current Insight into the Role of IL-35 and Its Potential Involvement in the Pathogenesis and Therapy of Atopic Dermatitis

“…IL-12Rβ2 is expressed on the surface of activated T cells, NK cells, B cells, and dendritic cells [ 15 , 16 , 17 , 18 ]. The IL-12Rβ2 subunit is undetectable on naive resting CD4+ T cells but its expression may be significantly altered by different molecules.…”

“…Interestingly, unlike transforming growth factor-β (TGF-β), which is constitutively expressed, IL-35 is suggested to be expressed in human tissues in response to inflammation [ 11 ]. However, a recent study on mice models has revealed that IL-35 is constitutively produced by cells in the retina, including the photoreceptor rod cells and the cone cells, which indicate that its housekeeping functions maintain ocular immune privilege [ 15 ].…”