Tofacitinib Affects M1-like and M2-like Polarization and Tissue Factor Expression in Macrophages of Healthy Donors and IBD Patients

Isabelle Lethen; Kristina Lechner-Grimm; Michael Gabel; Annkathrin Knauss; Raja Atreya; Markus F Neurath; Benno Weigmann

doi:10.1093/ibd/izad290

Tofacitinib Affects M1-like and M2-like Polarization and Tissue Factor Expression in Macrophages of Healthy Donors and IBD Patients

Inflamm Bowel Dis. 2023 Dec 23:izad290. doi: 10.1093/ibd/izad290. Online ahead of print.

Authors

Isabelle Lethen¹, Kristina Lechner-Grimm^{1

2}, Michael Gabel¹, Annkathrin Knauss¹, Raja Atreya^{3

4}, Markus F Neurath^{3

4}, Benno Weigmann^{1

2}

Affiliations

¹ Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany.
² Medical Immunology Campus Erlangen, Friedrich-Alexander-University Erlangen- Nürnberg, Erlangen, Germany.
³ Medical Clinic 1, University Hospital Erlangen, Erlangen, Germany.
⁴ Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.

PMID: 38142236
DOI: 10.1093/ibd/izad290

Abstract

Background: Tofacitinib, as inhibitor of Janus kinases (JAK), interrupts the transmission of numerous pro-inflammatory cytokines involved in the pathogenesis of inflammatory bowel diseases (IBD). Therefore, tofacitinib provides a potent option to treat ulcerative colitis (UC). Besides the anti-inflammatory potential, inhibition of widespread JAKs carries the risk of side effects. Macrophages are involved in the form of different subtypes in inflammation, wound healing, and even coagulation. This study aimed to explore the balanced use of tofacitinib in M1-like as well as M2-like macrophages of healthy donors and patients with IBD.

Methods: Monocytes of healthy donors and patients with chronic courses of IBD were obtained from blood samples. Macrophage colony-stimulating factor (M-CSF)-derived macrophages were treated with tofacitinib (1 µM, 5 µM, 10 µM) and polarized with either lipopolysaccharide and interferon (IFN)-γ towards M1-like-phenotype or with interleukin (IL)-4 towards M2-like-phenotype. ELISA and flow cytometry were used to evaluate cytokine levels and surface molecules.

Results: Tofacitinib had a modulating effect on M1-like macrophages whereby the effect on pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-12, IL-23) was less pronounced than the induction of anti-inflammatory IL-10. However, during M2-like polarization tofacitinib impaired the development of the corresponding phenotype becoming evident through decreased IL-10 levels and CD206 expression in treated macrophages. In both phenotypes, tofacitinib strongly downregulated the expression of immunostimulatory molecules (CD80, CD86, CD83, CD40). Furthermore, a dose-dependent correlation between treatment with tofacitinib and expressed tissue factor was noticed.

Conclusions: Tofacitinib influences both polarizations (M1/M2) and the expression of tissue factor in a dose-dependent manner.

Keywords: IBD; macrophages; tissue factor; tofacitinib.

Plain language summary

This study revealed a dose-dependent effect of tofacitinib on both M1-like and M2-like polarization, resulting in a decreased development of the corresponding phenotype. Furthermore, the applied dose of tofacitinib correlated with the expressed tissue factor in M1-like macrophages.

Abstract

Plain language summary

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