JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression

Abstract

Opportunistic fungal infections are a leading cause of death for immune-compromised patients and there is pressing need to develop new anti-fungal therapeutic agents because of toxicity and resistance to current anti-fungal drugs. Although C-type lectin receptor- and Toll-like receptor-induced signaling pathways are key activators of host anti-fungal immunity, little is known about the negative regulation of these immune responses. Here, we found that JNK1 activation suppresses anti-fungal immunity in mice. We showed that JNK1-deficient mice had significantly higher survival rate in response to Candida albicans infection, and JNK1 expressed in hematopoietic innate immune cells is critical for this effect. JNK1 deficiency leads to significantly higher induction of CD23, a novel C-type lectin receptor, through NFATc1-mediated regulation of the CD23 promoter. Blocking CD23 upregulation or CD23-dependent nitric oxide production eliminated the enhanced anti-fungal effect in JNK1-deficient mice. Notably, JNK inhibitors exerted potent anti-fungal therapeutic effects in Candida albicans-infected mouse and human cells, indicating that JNK1 can be a therapeutic target for treating fungal infection.

Immunity against fungi

“…CD23 binds α-mannans and β-glucans and induces the antifungal effector NOS2. Consistent with this model, Cd23 -/-mice are susceptible to systemic candidiasis (40). In otherwise nonphagocytic cells, dectin-1 expression promotes phagocytosis of nonopsonized β-glucan particles (5, 9).…”

“…This pathway regulates macrophage IL-6, IL-1β, and TNF, but not IL-12 responses, and is protective during systemic candidiasis (39). c-JUN kinase isoform 1-deficient (JNK1-deficient) mice are resistant to systemic candidiasis (40). Dectin-1-induced JNK1 signaling negatively regulates CD23 (encoded by Fcer2) expression via nuclear factor of activated T cells (NFAT) activation.…”

The antifungal pipeline: a reality check

“…Another fascinating example of work in immune cell antifungals is in targeting JUN amino-terminal kinase 1 (JNK1; also known as MAPK8), which has an important role in T cell activation and T helper cell differentiation. JNK1 negatively regulates the host antifungal innate immune response, and JNK1 inhibitors exert potent antifungal therapeutic effects both in mice and in human cells 130 . Finally, unlike for viral and bacterial infections, currently there is no commercial fungal vaccine for humans.…”

Antifungal Innate Immunity: A Perspective from the Last 10 Years

“…Importantly, treatment with 2 different JNK inhibitors significantly increased survival of C. albicans -infected mice, suggesting their potential use as a novel antifungal therapy (Fig. 1) [12]. …”