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ATP/P2X7r axis mediates the pathological process of allergic asthma by inducing M2 polarization of alveolar
Ruiting Li1, You Shang1, Xuemei Hu2
1Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, PR China.
Abstract:
Recent studies revealed that macrophages are polarized towards the M2 phenotype in an ovalbumin (OVA)-induced asthmatic model. Alveolar macrophages (AMs) are immune barriers in alveoli to various pathogens in the respiratory tract; AMs suppress Th2 cell proliferation, inhibit interleukin (IL)-4, IL-5, and IL-13 secretion, and protect against airway hyperresponsiveness in allergic asthma. However, the polarization status and effects of different types of AMs in the pathogenesis of asthma are not known. ATP/P2X7r, expressed mainly on macrophages and dendritic cells, is associated with acute and chronic asthmatic airway inflammation and Th2 immune responses in mice and humans and functions by activating the NLRP3 inflammasome complex and inducing proinflammatory cytokine release (IL-1β and IL-18). Therefore, we evaluated the association between the ATP/P2X7r axis and different types of AMs in the pathology of allergic asthma. A murine AM-depleted asthma model was established by administration of clodronate-encapsulated liposomes, and M1-or M2-AMs were adoptively transferred to confirm the effects of different AMs in allergic asthma. Brilliant Blue G and BzATP were administered to OVA/HDM-induced mice in vivo. Lipopolysaccharide + OVA, ATP, Brilliant Blue G, and BzATP were used to stimulate AMs isolated from control and asthmatic mice. We found that selective depletion of AMs aggravated lung inflammation in asthmatic mice. Further, M2-type AMs may play a key role in mediating asthmatic inflammatory responses via the adoptive transfer of M2-type AMs to AM-depleted asthmatic mice, and the phenotype of AMs differentiated to M2 type in asthma. P2X7r expression in M2-type AMs was higher than that in M1-type AMs. Activating P2X7r induced polarization of M2-type AMs and inhibited polarization of M1-type AMs, while blockage of P2X7r had the opposite effect. The ATP/P2X7r axis may participate in the pathogenesis of asthma by mediating the M2-type AM polarization.
Insights
Alveolar macrophages (AMs) polarize to M2 types in asthma, exacerbating inflammation. The ATP/P2X7r axis drives this M2 polarization, suggesting it as a therapeutic target for allergic asthma.
Area of Science:
- Immunology
- Respiratory Medicine
- Cell Biology
Background:
- Macrophages, particularly alveolar macrophages (AMs), play a critical role in respiratory tract immunity.
- In ovalbumin (OVA)-induced asthma models, AMs are known to polarize towards the M2 phenotype.
- The ATP/P2X7 receptor (P2X7r) axis is implicated in asthmatic inflammation and Th2 responses.
Purpose of the Study:
- To investigate the association between the ATP/P2X7r axis and AM polarization in allergic asthma pathogenesis.
- To determine the specific roles of M1 and M2 AM phenotypes in asthma.
- To explore the therapeutic potential of targeting the ATP/P2X7r axis.
Main Methods:
- Established a murine AM-depleted asthma model using clodronate-encapsulated liposomes.
- Adoptive transfer of M1 or M2 AMs to assess their effects in asthmatic mice.
- In vivo and in vitro stimulation with OVA, HDM, ATP, Brilliant Blue G, and BzATP to analyze AM polarization and P2X7r activity.
Main Results:
- Selective depletion of AMs worsened lung inflammation in asthmatic mice.
- M2-type AMs were identified as key mediators of asthmatic inflammatory responses.
- P2X7r expression was higher in M2-AMs; its activation promoted M2 polarization and inhibited M1 polarization, while blockage had opposite effects.
Conclusions:
- Alveolar macrophages differentiate into the M2 phenotype during asthma.
- The ATP/P2X7r axis is a critical regulator of M2-type AM polarization in allergic asthma.
- Targeting the ATP/P2X7r axis may offer a novel therapeutic strategy for managing allergic asthma.
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