Interleukin-36 potently stimulates human M2 macrophages, Langerhans cells and keratinocytes to produce pro-inflammatory cytokines.
Interleukin (IL)-36 cytokines belong to the IL-1 family and include three agonists, IL-36 α, β and γ and one inhibitor, IL-36 receptor antagonist (IL-36Ra). IL-36 and IL-1 (α and β) activate similar intracellular pathways via their related heterodimeric receptors, IL-36R/IL-1RAcP and IL-1R1/IL-1RAcP, respectively. However, excessive IL-36 versus IL-1 signaling induces different phenotypes in humans, which may be related to differential expression of their respective receptors. We examined the expression of IL-36R, IL-1R1 and IL-1RAcP mRNA in human peripheral blood, tonsil and skin immune cells by RT-qPCR. Monocyte-derived dendritic cells (MDDC), M0, M1 or M2-polarized macrophages, primary keratinocytes, dermal macrophages and Langerhans cells (LC) were stimulated with IL-1β or IL-36β. Cytokine production was assessed by RT-qPCR and immunoassays. The highest levels of IL-36R mRNA were found in skin-derived keratinocytes, LC, dermal macrophages and dermal CD1a(+) DC. In the blood and in tonsils, IL-36R mRNA was predominantly found in myeloid cells. By contrast, IL-1R1 mRNA was detected in almost all cell types with higher levels in tonsil and skin compared to peripheral blood immune cells. IL-36β was as potent as IL-1β in stimulating M2 macrophages, keratinocytes and LC, less potent than IL-1β in stimulating M0 macrophages and MDDC, and exerted no effects in M1 and dermal macrophages. Levels of IL-1Ra diminished the ability of M2 macrophages to respond to IL-1. Taken together, these data are consistent with the association of excessive IL-36 signaling with an inflammatory skin phenotype and identify human LC and M2 macrophages as new IL-36 target cells.
Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland; Division of Rheumatology, University Hospital Geneva, Switzerland.
Damien
D
Dietrich
Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland; Division of Rheumatology, University Hospital Geneva, Switzerland.
Praxedis
P
Martin
Unit of Immunopathology and Therapeutic Chemistry, Institute of Cellular and Molecular Biology, Strasbourg, France.
Vincent
V
Flacher
Inflammation Research, Amgen Inc., South San Francisco, CA, USA.
Yu
Y
Sun
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
David
D
Jarrossay
Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland; Division of Dermatology, University Hospital Geneva, Switzerland.
Nicolo
N
Brembilla
Unit of Immunopathology and Therapeutic Chemistry, Institute of Cellular and Molecular Biology, Strasbourg, France.
Christopher
C
Mueller
Inflammation Research, Amgen Inc., South San Francisco, CA, USA.
Heather A
HA
Arnett
Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland; Division of Rheumatology, University Hospital Geneva, Switzerland.
Gaby
G
Palmer
Inflammation Research, Amgen Inc., South San Francisco, CA, USA.
Jennifer
J
Towne
Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland; Division of Rheumatology, University Hospital Geneva, Switzerland. Electronic address: cem.gabay@hcuge.ch.
Cem
C
Gabay
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053577:Interleukin-1 Receptor Accessory Protein / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D007801:Langerhans Cells / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism*; D012867:Skin / Q000378:metabolism
D053577:Interleukin-1 Receptor Accessory Protein; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053573:Receptors, Interleukin-1 Type I; C571244:interleukin-36 receptor, human
IL-1; IL-1R1; IL-36; IL-36R; Myeloid cells; Skin