Research ArticleINNATE IMMUNITY

Skin infections are eliminated by cooperation of the fibrinolytic and innate immune systems

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Science Immunology  22 Sep 2017:
Vol. 2, Issue 15, eaan2725
DOI: 10.1126/sciimmunol.aan2725

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There’s more than one way to skin an infection

There are two phases of innate immune control of skin infection by Candida albicans—protective containment and elimination. Now, Santus et al. report that early activation of the transcript factor nuclear factor of activated T cells (NFAT) balances these two phases. During the containment phase, NFAT regulates active TGF-β expression, which induces collagen deposition and traps the microbe. During the elimination phase, NFAT induces IFN-γ that promotes skin ulceration and microbial expulsion. These functions are not restricted to Candida because cross-talk between the innate immune and fibrinolytic responses also contributed to defense against Staphylococcus aureus. This cooperation is critical to minimizing tissue damage while fighting infection.

Abstract

Nuclear factor of activated T cells (NFAT) is activated in innate immune cells downstream of pattern recognition receptors, but little is known about NFAT’s functions in innate immunity compared with adaptive immunity. We show that early activation of NFAT balances the two major phases of the innate response to Candida albicans skin infections: the protective containment (abscess) and the elimination (expulsion) phases. During the early containment phase, transforming growth factor–β (TGF-β) induces the deposit of collagen around newly recruited polymorphonuclear cells to prevent microbial spreading. During the elimination phase, interferon-γ (IFN-γ) blocks differentiation of fibroblasts into myofibroblasts by antagonizing TGF-β signaling. IFN-γ also induces the formation of plasmin that, in turn, promotes abscess capsule digestion and skin ulceration for microbial discharge. NFAT controls innate IFN-γ production and microbial expulsion. This cross-talk between the innate immune and the fibrinolytic systems also occurs during infection with Staphylococcus aureus and is a protective response to minimize tissue damage and optimize pathogen elimination.

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