Acinetobacter species in the skin microbiota protects from allergic sensitization and inflammation - 26/09/14

Doi : 10.1016/j.jaci.2014.07.059

Nanna Fyhrquist, PhD ^a, Lasse Ruokolainen, PhD ^b, Alina Suomalainen, BSc ^a, Sari Lehtimäki, PhD ^c, Ville Veckman, PhD ^a, Johanna Vendelin, PhD ^a, Piia Karisola, PhD ^a, Maili Lehto, PhD ^a, Terhi Savinko, PhD ^d, Hanna Jarva, MD ^e, Timo U. Kosunen, MD ^e, Jukka Corander, PhD ^f, Petri Auvinen, PhD ^d, Lars Paulin, PhD ^d, Leena von Hertzen, PhD ^g, Tiina Laatikainen, PhD ^h,ⁱ, Mika Mäkelä, MD ^g, Tari Haahtela, MD ^g, Dario Greco, PhD ^a, Ilkka Hanski, PhD ^b, Harri Alenius, PhD ^a,^⁎
^a Unit of Systems Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland
^b Department of Biosciences, University of Helsinki, Helsinki, Finland
^d Institute of Biotechnology, University of Helsinki, Helsinki, Finland
^c Molecular Immunology Group, Turku Centre for Biotechnology, Turku, Finland
^e Haartman Institute, Department of Bacteriology and Immunology and Research Programs Unit, Immunobiology, University of Helsinki, and Helsinki University Central Hospital Laboratory (HUSLAB), Helsinki, Finland
^f Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland
^g Allergy Department, Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland
^h Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
ⁱ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

^∗Corresponding author: Harri Alenius, PhD, Unit of Systems Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 b, Helsinki-FIN 00250, Finland.

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Abstract

Background

The human commensal microbiota interacts in a complex manner with the immune system, and the outcome of these interactions might depend on the immune status of the subject.

Objective

Previous studies have suggested a strong allergy-protective effect for Gammaproteobacteria. Here we analyze the skin microbiota, allergic sensitization (atopy), and immune function in a cohort of adolescents, as well as the influence of Acinetobacter species on immune responses in vitro and in vivo.

Methods

The skin microbiota of the study subjects was identified by using 16S rRNA sequencing. PBMCs were analyzed for baseline and allergen-stimulated mRNA expression. In in vitro assays human monocyte-derived dendritic cells and primary keratinocytes were incubated with Acinetobacter lwoffii. Finally, in in vivo experiments mice were injected intradermally with A lwoffii during the sensitization phase of the asthma protocol, followed by readout of inflammatory parameters.

Results

In healthy subjects, but not in atopic ones, the relative abundance of Acinetobacter species was associated with the expression of anti-inflammatory molecules by PBMCs. Moreover, healthy subjects exhibited a robust balance between anti-inflammatory and T_H1/T_H2 gene expression, which was related to the composition of the skin microbiota. In cell assays and in a mouse model, Acinetobacter species induced strong T_H1 and anti-inflammatory responses by immune cells and skin cells and protected against allergic sensitization and lung inflammation through the skin.

Conclusion

These results support the hypothesis that skin commensals play an important role in tuning the balance of T_H1, T_H2, and anti-inflammatory responses to environmental allergens.

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Key words : Atopy, Gammaproteobacteria, Acinetobacter species, PBMC, anti-inflammatory gene expression, dendritic cells, keratinocytes, mouse asthma model

Abbreviations used : ACTB, AHR, DC, FOXP3, GAPDH, moDC, OVA, PE, qPCR, TLR2, Treg

Plan

Methods

Study subjects and atopic sensitization

Skin microbiota

PBMCs

Microbes for in vitro and in vivo experiments

In vitro cell assays

Real-time quantitative PCR and Luminex

Animal model

Statistical analysis

Results

Associations between the skin microbiota and PBMC gene expression

Association of anti-inflammatory responses with Acinetobacter species

Balanced proinflammatory and anti-inflammatory responses in healthy subjects

Acinetobacter species–induced immune responses in vitro

Acinetobacter species–induced protective immune responses in vivo

Discussion

The research leading to these results has received funding from the Academy of Finland (grants nos. 138695, 255350, 121025, and 251170), the European Research Council (grant no. 239784), the Jane and Aatos Erkko Foundation, Helsinki University Hospital (HUS) (grant no. 8361), and by the European Union's Seventh Framework Programme FP7/2007-2013 under grant agreements 261366 (MAARS) and 261357 (MeDALL).

Disclosure of potential conflict of interest: This study was funded by the Academy of Finland (grants nos. 138695, 255350, 121025, and 251170), the European Research Council (grant no. 239784), the Jane and Aatos Erkko Foundation, the European Union's Seventh Framework Programme (grant agreements 261366 and 261357), and the Helsinki University Hospital (grant no. 8361). T. Haahtela is on the board of the Global Initiative for Asthma, and has received payment for delivering lectures from OrionPharma and Merck. The rest of the authors declare that they have no relevant conflicts of interest.