A JAK1 Selective Kinase Inhibitor and Tofacitinib Affect Macrophage Activation and Function

Area of Science:

• Immunology
• Pharmacology
• Gastroenterology

Background:

• Janus kinases (JAKs) are critical mediators of cytokine signaling implicated in inflammatory bowel disease (IBD) pathogenesis.
• Tofacitinib, a broad-spectrum JAK inhibitor, demonstrates efficacy in ulcerative colitis but raises safety concerns due to off-target effects.
• Development of selective JAK inhibitors is crucial for targeted therapy, especially considering the role of myeloid cells in intestinal immunity.

Purpose of the Study:

• To investigate the impact of selective JAK1 and JAK3 inhibitors, alongside tofacitinib, on macrophage polarization (M1/M2) and function.
• To evaluate the therapeutic potential of JAK inhibitors in experimental models of colitis.

Main Methods:

• Macrophages and monocytes were treated with JAK1-selective inhibitor (JAK1i), JAK3-selective inhibitor (JAK3i), and tofacitinib.
• Transcriptional, functional, and metabolic analyses were performed to assess macrophage polarization and activity.
• In vivo studies involved oral administration of JAK1i and tofacitinib in dextran sodium sulfate (DSS)-induced acute and acute rescue colitis models.

Main Results:

• Tofacitinib and JAK1i, but not JAK3i, inhibited M1 macrophage polarization markers and interferon gamma-induced transcripts.
• A phenotypic switch towards M2-like macrophages was observed, accompanied by enhanced oxidative phosphorylation.
• In vivo, JAK1i and tofacitinib did not prevent acute DSS colitis but improved weight recovery and disease activity in the acute rescue model.

Conclusions:

• JAK1 inhibition, by tofacitinib or JAK1i, induces anti-inflammatory macrophage phenotypes, highlighting JAK1 as a key pathway.
• Selective JAK1 inhibition offers a potential therapeutic strategy for inflammatory conditions.
• JAK1i and tofacitinib show modest benefits in ameliorating established DSS-induced colitis, suggesting a role in disease recovery.