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.