Discussion
Our findings indicate that CXCR1 and CXCR2 play a major role in Th2 and Th17- mediated allergic lung inflammation. These receptors play a critical role in the recruitment of CXCR1- and CXCR2-expressing Th2 cells, Th17 cells, eosinophils, and neutrophils. We show for the first time that allosteric inhibition of CXCR1 and CXCR2 by oral administration of ladarixin potently inhibits Th2 and Th17-mediated allergic lung inflammation.
A growing number of monoclonal antibodies that target either a single Th2 cytokine or its cognate receptor are currently used to treat patients with severe asthma. Thus monoclonal antibodies block IL5 (mepolizumab50 and reslizumab51), IL5 receptor alpha-chain (benralizumab52,53), and IL4 receptor alpha (dupilumab54) are currently used in the management of severe asthma. IL17-secreting Th17 cells also contribute to airway remodeling and disease severity in severe endotype asthma2,3. Biologics that block IL17 have been or are being tried in this asthma phenotype55,56. Unexpectedly, administration of the anti-IL17 receptor antibody brodalumab to the subjects with moderate to severe asthma failed to improve the clinical symptoms55. A number of studies indicate a crucial role of IL23 in maintaining Th17 cells39, and regulating Th2 and Th17 cells57,58. Thus lack of IL23 suppressed naïve Th cell differentiation toward Th2 cells57, and treatment with anti-IL23 antibody suppressed ovalbumin-induced IL5 and IL13 production and eosinophil recruitment58. In the Th2/Th17 dominant subgroup of severe asthma42,43, BALF levels of IL23 were elevated43. These studies suggest that inhibiting IL23 with a monoclonal antibody should be beneficial in asthma. However, a clinical trial of human anti–IL23p19 monoclonal antibody risankizumab demonstrated that it had no beneficial effect in patients with severe asthma59. Thus, at this time, there is no effective treatment for Th17-associated allergic lung inflammation. Our results suggest that allosteric inhibition of CXCR1 and CXCR2 may suppress Th17-associated allergic inflammation.
A focus of earlier studies of CXCR1/2 inhibitors in mitigating neutrophil recruitment in allergic inflammation30,31. In addition to our novel finding that allosteric inhibition of CXCR1 and CXCR2 blocks the recruitment of Th2 and Th17 cells, we show that ladarixin suppresses the recruitment of neutrophils, including IL23-secreting neutrophils. These data build on our earlier report that neutrophils can augment allergic airway inflammation and sensitization30. Other studies have shown that neutrophil recruitment to the site is closely associated with local allergic inflammation in atopic dermatitis60, allergic contact dermatitis61,62, anaphylaxis63, and asthma30,64by regulating innate and adaptive immunity. Since neutrophils express abundant CXCR1 and CXCR2, inhibition of their recruitment likely also contributes to ladarixin-induced mitigation of allergic lung inflammation.
Allergenic extracts stimulate Toll-like receptor 4/Myd88-dependent ROS generation and oxidative DNA damage34,47. Oxidative stress stimulates ROS-generating neutrophils recruitment via CXCL1/2-CXCR1/2 axis30,31which in turn facilitates allergic airway inflammation30. Administration of ladarixin suppressed CDE challenge-induced lung DNA damage likely via two mechanisms. First, since stimulation of CXCR2 induces ROS generation65, ladarixin may directly suppress ROS generation from CXCR2-expressing cells. Second, ladarixin inhibits the recruitment of CXCR1/2-expressing ROS-generating inflammatory cells, such as neutrophils and eosinophils. Since oxidative DNA damage in the lung facilitates allergic inflammation30,34, ladarixin might suppress allergic inflammation by inhibiting DNA damage and augmenting genome integrity.
Ladarixin is a dual CXCR1/2 antagonist that demonstrated beneficial effects on tumors and endocrine disorders. Treatment with ladarixin inhibited the melanoma xenografts in vivo 32, delayed and prevented spontaneous diabetes onset in NOD mice66, and when administered with an immune checkpoint inhibitor like anti-PD-1 inhibited tumor growth and improved the survival in tumor xenograft mouse model67. Based on the clinical trial recently performed in patients with new-onset type 1 diabetes, the use of ladarixin is safe and well tolerated68. We suggest that future human studies should carefully investigate the role of allosteric inhibition of CXCR1 and CXCR2 are a novel approach to mitigating allergic inflammation involving activation of Th2-and Th17-cells and pathways.