Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity

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Significance

We found that among chemokine family members, only CXCL14 is abundantly produced in epidermal keratinocytes in a circadian rhythm-dependent manner. Whereas in nocturnal mice, CXCL14 expression was high during the day and low at night, in diurnal marmosets, expression was low during the daytime and high at night. Rhythmically expressed CXCL14 binds to bacterial DNA, leading to pathogen DNA-mediated Toll-like receptor 9 activation and promotion of phagocytosis, in this way serving to protect skin from overproliferation of the pathogen. We propose that during the resting period of animals, epidermis-derived CXCL14 acts on resident immune cells to regulate the skin’s innate immunity.

Abstract

The epidermis is the outermost layer of the skin and the body’s primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.

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Most cited references 54

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Next-generation sequencing approaches have yielded new insights into circadian function. Here, Takahashi reviews genome-wide analyses of the clock transcriptional feedback loop in mammals, which reveal a global circadian regulation of transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription and chromatin remodelling.

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DNA from bacteria has stimulatory effects on mammalian immune cells, which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immuno-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells. TLR9-/- mice showed resistance to the lethal effect of CpG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (publisher-id): pnas

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Electronic): 15 June 2022

Publication date (Print): 21 June 2022

Publication date PMC-release: 15 December 2022

Volume: 119

Issue: 25

Electronic Location Identifier: e2116027119

Affiliations

[1] ^aGraduate School of Pharmaceutical Sciences, Kyoto University , Kyoto 606-8501, Japan;

[2] ^bDepartment of Dermatology, Graduate School of Medicine, Kyoto University , Kyoto 606-8501, Japan;

[3] ^cStem Cell Project, Tokyo Metropolitan Institute of Medical Science , Tokyo 156-8506, Japan;

[4] ^dDepartment of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine , Kyoto 602-8566, Japan;

[5] ^eGraduate School of Frontier Biosciences, Osaka University , Osaka 565-0871, Japan;

[6] ^fGraduate School of Medical and Dental Sciences, Tokyo Medical and Dental University , Tokyo 113-8510, Japan;

[7] ^gCore Technology and Research Center, Tokyo Metropolitan Institute of Medical Science , Tokyo 156-8506, Japan;

[8] ^hOral Health Science Research Center, Graduate School of Kanagawa Dental University , Kanagawa 238-8580, Japan;

[9] ⁱInstitute for the Advanced Study of Human Biology, Kyoto University Institute for Advanced Study, Kyoto University , Kyoto 606-8501, Japan;

[10] ^jThe Hakubi Center for Advanced Research, Kyoto University , Kyoto 606-8501, Japan;

[11] ^kDepartment of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University , Kyoto 606-8501, Japan;

[12] ^lDepartment of Neuroscience, Graduate School of Medicine, Kyoto University , Kyoto 606-8501, Japan;

[13] ^mGraduate School of Science, Department of Biological Science, Tokyo Metropolitan University , Tokyo 192-0397, Japan

Author notes

²To whom correspondence may be addressed. Email: hara-tk@ 123456igakuken.or.jp or okamura.hitoshi.4u@ 123456kyoto-u.ac.jp .

Edited by Jay Dunlap, Geisel School of Medicine at Dartmouth, Hanover, NH; received August 31, 2021; accepted April 20, 2022

Author contributions: T.H. and H.O. designed research; K. Tsujihana, K. Tanegashima, Y.S., H.Y., S.A., R.N., K. Tominaga, R.S., I.M., Y.K., M.S., and H.O. performed research; K. Tominaga, Y.N., R.-I.H., T.N., M.T., G.E., T.I., and K.K. contributed new reagents/analytic tools; K. Tsujihana, K. Tanegashima, Y.S., H.Y., R.N., K. Tominaga, Y.N., R.-I.H., T.N., M.T., G.E., M.D., T.I., K.K., T.H., and H.O. analyzed data; and K. Tsujihana, K. Tanegashima, T.H., and H.O. wrote the paper.

¹K. Tsujihana and K. Tanegashima contributed equally to this work.

Author information

Kojiro Tsujihana https://orcid.org/0000-0002-8701-3706

Kosuke Tanegashima https://orcid.org/0000-0001-8733-8538

Sota Akazawa https://orcid.org/0000-0001-9655-9690

Ryu-Ichiro Hata https://orcid.org/0000-0003-1455-8585

Tomonori Nakamura https://orcid.org/0000-0002-0173-0780

Gyohei Egawa https://orcid.org/0000-0002-6101-4719

Masao Doi https://orcid.org/0000-0001-6264-9217

Tadashi Isa https://orcid.org/0000-0001-5652-4688

Takahiko Hara https://orcid.org/0000-0002-6565-0720

Hitoshi Okamura https://orcid.org/0000-0002-3013-4881

Article

Publisher ID: 202116027

DOI: 10.1073/pnas.2116027119

PMC ID: 9231475

PubMed ID: 35704759

SO-VID: 1531f8fe-7b2e-4d0b-b41a-6009d9bee5af

License:

This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

History

Date accepted : 20 April 2022