Mast cell–airway smooth muscle interactions play a key role in the pathogenesis of asthma . Mast cells (MCs) are an important effector cell of the immune system. When activated, they degranulate utilising a calcium channel switch releasing a store of pro-inflammatory mediators, thereby amplifying inflammation . MCs also express a plethora of chemokine receptors which allow for spatial and temporal migration and undergo tissue-specific maturation .
Airway smooth muscle (ASM) cells contribute to asthma through their contractile, proliferative and synthetic properties . They release a variety of inflammatory mediators including MC-responsive chemokines and cytokines . Excessive numbers of activated MCs localise to ASM in asthma  and numbers of colocalised mast cells are found to associate with bronchial hyper-responsiveness which might also be a contributing factor to disease severity [6-9].
So what causes the increased localisation of MCs to ASM in asthma? There are two possibilities either ASM cells from asthmatic subjects produce an excess of mast cell chemoattractants or alternatively they lack an inhibitory factor which normally inhibits mast cell recruitment. There is some evidence from previous work for the former that that ASM cells from asthmatic subjects synthesise increased amounts of MC chemoattractants. Mast cell lines migrate in higher numbers to conditioned media (CM) from asthmatic compared to non-asthmatic ASMs stimulated with an IL-1β and T-helper (Th)1 (TNFα and IFNγ) cytokines. This is driven by CXCL10 (IP-10) which is produced in greater amounts by asthmatic ASM . However, a reduction in MC chemotaxis inhibitors in asthmatic ASM could also be involved. Experiments involving titration of asthmatic ASM CM with non-asthmatic ASM CM inhibited MC chemotaxis to a greater extent than titrating with medium alone suggesting a negative regulator might be expressed by normal ASMs to keep MC chemotaxis under control .
So what does the current study add to the story? Alkhouri and colleagues  set out to identify which factors expressed in normal (non-asthmatic) ASM might inhibit MC chemotaxis. From an array of 120 cytokines, CXCL1 (Gro-α) was the only factor expressed in abundance by Th1-stimulated non-asthmatic ASMs compared to asthmatic ASMs with differing temporal regulation, a novel finding.
In vitro experiments by the authors identified CXCL1 as a negative regulator of MC chemotaxis. Specifically, addition of exogenous CXCL1 was able to inhibit human mast cell line (HMC-1) chemotaxis induced by CXCL10 and CXCL8 and by asthmatic ASM CM stimulated with a Th1 or Th2 panel of cytokines in both HMC-1 and primary human lung mast cells (HLMCs). Inhibiting CXCL1 in CM from non-asthmatic cells increased MC chemotaxis. In contrast, similar experiments in asthmatic cells did not significantly affect chemotaxis. Blocking CXCR2 the receptor for CXCL1 ligand binding in MCs increased chemotaxis towards non-asthmatic ASM CM, but not towards asthmatic ASM CM.
The authors then investigated a mechanism for these findings namely that CXCL1: CXCR2 binding could interact with calcium signalling in MCs. CXCL1 inhibited intracellular calcium mobilisation in HMC-1 induced by CM from asthmatic ASMs stimulated with Th1 and Th2 cytokines . This suggests there is a defect in the CXCL1 axis in asthma that acts as a protective brake in normal ASM and so the increased MC accumulation in asthma is due at least in part to a failure of the inhibitory mechanism.
This study has improved upon the knowledge of MC–ASM interaction by demonstrating that non-asthmatics can dampen down mast cell chemotaxis to ASMs via release of CXCL1 induced by IL-1β and Th1 or Th2 cytokines. This involved signalling through CXCR2 on MCs and reducing their intracellular calcium mobilisation. If MC recruitment could be reduced or activity repressed this would offer a therapeutic potential for asthma.
There are a number of drugs in current clinical use that might already target mast cell function such as β2-agonists  and glucocorticoids . Blockade of KCa3.1 channels on MCs by the drug TRAM-34 markedly alters mast cell chemotaxis and is a promising therapeutic agent in asthma [14, 15]. Would it be possible to upregulate the defective CXCL1 in asthmatic ASM cells? One of the pathways regulating CXCL1 expression is through the activation of JNK MAP kinase which is known to be defective in asthmatic ASM . Although activation of JNK signalling might induce CXCL1 in asthmatic ASM, it is likely to have a number of unwanted effects. Development of a non-peptide agonist for the CXCR2 receptor on MCs could offer an alternative but only a partial agonist, VUF10948 currently exists .
More extensive mechanistic studies would be helpful to elucidate this abnormality of MC migration to ASM in asthmatics. Given that HLMCs in this study  were extracted from normal donors, it would be useful to replicate these findings in vitro with primary MCs from asthmatics as expression of CXCR2 could be altered by mast cell status when resident on asthmatic ASMs . We also know there are differences in the genetic profile of asthmatics that might help explain the current findings . Overall, however, this is an interesting paper that offers new insight into how faulty localisation of mast cells in ASM occurs in asthma.
Conflict of interest: The authors declare no conflict of interest.