James A. Sanford, Ling-Juan Zhang, Michael R. Williams, Jon A. Gangoiti,
Chun-Ming Huang, Richard L. Gallo
Epidermal keratinocytes participate in immune defense through their capacity to recognize danger, trigger inflammation,
and resist infection. However, normal skin immune function must tolerate contact with an abundant community
of commensal microbes without inflammation. We hypothesized that microbial environmental conditions dictate the
production of molecules that influence epigenetic events and cause keratinocytes to break innate immune tolerance.
Propionibacterium acnes, a commensal skin bacterium, produced the short-chain fatty acids (SCFAs) propionate and
valerate when provided a lipid source in hypoxic growth conditions, and these SCFAs inhibited histone deacetylase
(HDAC) activity. Inhibition of HDAC activity in keratinocytes promoted cytokine expression in response to Toll-like
receptor (TLR) ligands for TLR2 or TLR3. This response was opposite to the action of HDAC inhibition on production
of inflammatory cytokines bymonocytes and involved HDAC8 and HDAC9 because small interfering RNA silencing of
these HDACs recapitulated the activity of SCFAs. Analysis of cytokine expression in mice confirmed the response of the
epidermis where application of SCFA on the skin surface promoted cytokine expression, whereas subcutaneous
administration was inhibitory. These findings show that the products of commensal microbes made under specific
conditions will inhibit HDAC activity and break tolerance of the epidermis to inflammatory stimuli.
Sanford et al., Sci. Immunol. 1, eaah4609 (2016) 28 October 2016
Zhang LJ, Gallo RL
Antimicrobial peptides and proteins (AMPs) are a diverse class of naturally occurring molecules that are produced as a first line of defense by all multicellular organisms. These proteins can have broad activity to directly kill bacteria, yeasts, fungi, viruses and even cancer cells. Insects and plants primarily deploy AMPs as an antibiotic to protect against potential pathogenic microbes, but microbes also produce AMPs to defend their environmental niche. In higher eukaryotic organisms, AMPs can also be referred to as 'host defense peptides', emphasizing their additional immunomodulatory activities. These activities are diverse, specific to the type of AMP, and include a variety of cytokine and growth factor-like effects that are relevant to normal immune homeostasis. In some instances, the inappropriate expression of AMPs can also induce autoimmune diseases, thus further highlighting the importance of understanding these molecules and their complex activities. This Primer will provide an update of our current understanding of AMPs.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Curr Biol. 2016 Jan 11;26(1):R14-9. doi: 10.1016/j.cub.2015.11.017.
PubMed (NCBI) References (link)