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Brief Report : Arthritis in KRN T Cell Receptor-Transgenic Mice Does Not Require Interleukin-17 or Th17 Cells. / Auger, Jennifer L; Cowan, Hannah M; Engelson, Brianna J; Kashem, Sakeen W; Prinz, Immo; Binstadt, Bryce A.
in: ARTHRITIS RHEUMATOL, Jahrgang 68, Nr. 8, 08.2016, S. 1849-55.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Brief Report
T2 - Arthritis in KRN T Cell Receptor-Transgenic Mice Does Not Require Interleukin-17 or Th17 Cells
AU - Auger, Jennifer L
AU - Cowan, Hannah M
AU - Engelson, Brianna J
AU - Kashem, Sakeen W
AU - Prinz, Immo
AU - Binstadt, Bryce A
N1 - © 2016, American College of Rheumatology.
PY - 2016/8
Y1 - 2016/8
N2 - OBJECTIVE: Th17 cells and interleukin-17 (IL-17) cytokine family members are implicated in the pathogenesis of many rheumatic diseases. Most studies in mouse models of inflammatory arthritis have demonstrated a key role for the proinflammatory cytokine IL-17A and its receptor, the IL-17 receptor (IL-17R) A/C heterodimer. The aim of this study was to use a rigorous genetic approach to evaluate the contribution of Th17 cells and IL-17 in the autoantibody-dependent KRN T cell receptor-transgenic mouse model of arthritis.METHODS: We bred KRN mice expressing the major histocompatibility complex class II molecule A(g7) (referred to as K/B/g7 mice) and genetically lacking the related cytokines IL-17A and IL-17F or their critical receptor subunit, IL-17RA. Using bone marrow transplantation, we generated mice in which hematopoietic cells from K/B/g7 donor mice lacked the key Th17-differentiating transcription factor, retinoic acid receptor-related orphan nuclear receptor γt (Rorγt).RESULTS: K/B/g7 mice lacking both IL-17A and IL-17F produced normal titers of pathogenic autoantibodies, and arthritis developed in a typical manner. Similarly, neither IL-17RA nor Rorγt expression by hematopoietic cells was required for disease development in this model.CONCLUSION: Despite prior reports suggesting that Th17 cells and IL-17A are crucially involved in the pathogenesis of arthritis in K/BxN mice, the results presented here provide genetic evidence that IL-17A and IL-17F, IL-17RA, and Rorγt expression by hematopoietic cells are dispensable for normal arthritis progression in the K/B/g7 mouse model system. We discuss potential explanations for the discrepancies between these 2 highly similar model systems. These findings plus those in other mouse models of arthritis provide insight regarding why therapeutic biologic agents targeting the Th17/IL-17 axis are beneficial in some human rheumatic diseases but not others.
AB - OBJECTIVE: Th17 cells and interleukin-17 (IL-17) cytokine family members are implicated in the pathogenesis of many rheumatic diseases. Most studies in mouse models of inflammatory arthritis have demonstrated a key role for the proinflammatory cytokine IL-17A and its receptor, the IL-17 receptor (IL-17R) A/C heterodimer. The aim of this study was to use a rigorous genetic approach to evaluate the contribution of Th17 cells and IL-17 in the autoantibody-dependent KRN T cell receptor-transgenic mouse model of arthritis.METHODS: We bred KRN mice expressing the major histocompatibility complex class II molecule A(g7) (referred to as K/B/g7 mice) and genetically lacking the related cytokines IL-17A and IL-17F or their critical receptor subunit, IL-17RA. Using bone marrow transplantation, we generated mice in which hematopoietic cells from K/B/g7 donor mice lacked the key Th17-differentiating transcription factor, retinoic acid receptor-related orphan nuclear receptor γt (Rorγt).RESULTS: K/B/g7 mice lacking both IL-17A and IL-17F produced normal titers of pathogenic autoantibodies, and arthritis developed in a typical manner. Similarly, neither IL-17RA nor Rorγt expression by hematopoietic cells was required for disease development in this model.CONCLUSION: Despite prior reports suggesting that Th17 cells and IL-17A are crucially involved in the pathogenesis of arthritis in K/BxN mice, the results presented here provide genetic evidence that IL-17A and IL-17F, IL-17RA, and Rorγt expression by hematopoietic cells are dispensable for normal arthritis progression in the K/B/g7 mouse model system. We discuss potential explanations for the discrepancies between these 2 highly similar model systems. These findings plus those in other mouse models of arthritis provide insight regarding why therapeutic biologic agents targeting the Th17/IL-17 axis are beneficial in some human rheumatic diseases but not others.
KW - Animals
KW - Interleukin-17/physiology
KW - Mice
KW - Mice, Transgenic
KW - Receptors, Antigen, T-Cell/genetics
KW - Th17 Cells/physiology
U2 - 10.1002/art.39646
DO - 10.1002/art.39646
M3 - SCORING: Journal article
C2 - 26882006
VL - 68
SP - 1849
EP - 1855
JO - ARTHRITIS RHEUMATOL
JF - ARTHRITIS RHEUMATOL
SN - 2326-5191
IS - 8
ER -
