Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients.

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T1 - Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients.

AU - Bergenfelz, Caroline

AU - Hagerling, Catharina

AU - Ekström, Elin

AU - Jirström, Karin

AU - Janols, Helena

AU - Wullt, Marlene

AU - Bredberg, Anders

AU - Leandersson, Karin

N1 - The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200), Experimental Pathology (013031100), Pathology, (Lund) (013030000), Infectious Diseases Research Unit (013242010), Clinical Microbiology, Malmö (013011000)

PY - 2012

Y1 - 2012

N2 - A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, Gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy.

AB - A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, Gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy.

U2 - 10.4049/jimmunol.1103378

DO - 10.4049/jimmunol.1103378

M3 - Article

VL - 188

SP - 5448

EP - 5458

JO - Journal of immunology (Baltimore, Md. : 1950)

JF - Journal of immunology (Baltimore, Md. : 1950)

SN - 1550-6606

IS - 11

ER -