Anti-inflammatory effects of the JAK inhibitor tofacitinib in two murine house dust mite -driven models of asthma.

The JAK/STAT signalling plays a key role in both innate and adaptive immunity and it has been reported that JAK inhibition can reduce allergen-induced airway inflammation in different animal models of asthma. Here we studied the effects of the JAK inhibitor tofacitinib, orally administered at 15 and 30 mg/kg b.i.d., in two HDM-induced mouse models of asthma, one sensitive (HDM/Alum) and the other insensitive to inhaled steroids (HDM/CFA): modulation of inflammatory cell recruitment and cytokines in BALF along with the lung STAT3 phosphorylation, as a target engagement marker of JAK inhibition, were evaluated. In the HDM/Alum model characterised by eosinophilic inflammation and Th2 cytokine profile, tofacitinib, administered only during the HDM challenge, significantly reduced eosinophil recruitment at 30 mg/kg (41 ± 8%, p<0.05). When administered during both the sensitisation and the challenge phase, tofacitinib produced a significant reduction of lung eosinophilia at both tested doses (55 ± 11%, p<0.001 at 15 mg/kg and 77 ± 7%, p<0.001 at 30 mg/kg). This effect was associated with a decrease of KC (55 ± 8%, p<0.05), IL-4 (62 ± 12%, NS), and GM-CSF (74 ± 17%, NS) at the dose of 30 mg/kg, along with a 46% reduction of phosphorylated STAT3. Conversely, in the HDM/CFA model, characterised by a predominant neutrophilic component and mixed Th1 and Th2 cytokine profile, tofacitinib failed to modulate inflammatory cell recruitment in BALF, even when administered during both the sensitisation and the challenge phase. Overall, these data suggest that the JAK/STAT pathway may represent a relevant target for eosinophilic allergic forms of asthma.