title: FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice.
abstract: FNDC4 is a secreted factor sharing high homology with the exercise-associated myokine irisin (FNDC5). Here we report that Fndc4 is robustly upregulated in several mouse models of inflammation as well as in human inflammatory conditions. Specifically, FNDC4 levels are increased locally at inflamed sites of the intestine of inflammatory bowel disease patients. Interestingly, administration of recombinant FNDC4 in the mouse model of induced colitis markedly reduces disease severity compared with mice injected with a control protein. Conversely, mice lacking Fndc4 develop more severe colitis. Analysis of binding of FNDC4 to different immune cell types reveals strong and specific binding to macrophages and monocytes. FNDC4 treatment of bone marrow-derived macrophages in vitro results in reduced phagocytosis, increased cell survival and reduced proinflammatory chemokine expression. Hence, treatment with FNDC4 results in a state of dampened macrophage activity, while enhancing their survival. Thus, we have characterized FNDC4 as a factor with direct therapeutic potential in inflammatory bowel disease and possibly other inflammatory diseases.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Madeleen
authors.initials: M
authors.lastname: Bosma
authors.affiliation: Department of Biosciences and Nutrition, Center of Innovative Medicine, Karolinska Institutet, Huddinge SE-141 83, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Gerling
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Pasto
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Georgiadi
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Evan
authors.initials: E
authors.lastname: Graham
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Shilkova
authors.affiliation: Division of Nephrology, Kanazawa University Hospital, Kanazawa 920-8641, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Iwata
authors.affiliation: Department of Medicine, Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm SE-171 76, Sweden.|GastroCentrum, Karolinska University Hospital, Solna, Stockholm SE-171 76, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Almer
authors.affiliation: Division of Medical Diagnostics, Ryhov County Hospital, Jönköping 55185, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Söderman
authors.affiliation: Department of Biosciences and Nutrition, Center of Innovative Medicine, Karolinska Institutet, Huddinge SE-141 83, Sweden.
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgård
authors.affiliation: Department of Medicine, Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm SE-171 76, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wermeling
authors.affiliation: Department of Dental Medicine, Karolinska Institutet, Huddinge SE-141 83, Sweden.
authors.forename: Elisabeth Almer
authors.initials: EA
authors.lastname: Boström
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Pontus Almer
authors.initials: PA
authors.lastname: Boström
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010587:Phagocytosis / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D005353:Fibronectins
chemical_list: D000893:Anti-Inflammatory Agents; D016264:Dextran Sulfate; D008565:Membrane Proteins; D011506:Proteins; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; C000610535:FNDC4 protein, human; D005353:Fibronectins; C470951:FNDC4 protein, mouse