CD39 and macrophage cells
Anna et al. defined macrophage extracellular purine metabolism as a
novel checkpoint in macrophage cell fate decision-making and an
attractive target to control pathological macrophages in immune-mediated
diseases [81]. The expression of CD39 and CD73 in
M2 macrophages was significantly higher than in pro-inflammatory M1
macrophages [82]. By regulating the concentration
of purine in the extracellular space, the CD39/CD73 system helps
fine-tune the differentiation and activity of macrophages. Moreover, the
lack of CD39 can lead to the accumulation of ATP, which stimulates
macrophages to release pro-inflammatory cytokines[83, 84]. Depletion of ATP by soluble CD39-like
apyrase suppressed macrophage phagocytosis in vitro[85]. In the presence of exogenously added ATP,
TLR-stimulated macrophages hydrolyze ATP via CD39 to regulate their own
activation state, and the loss of CD39 expression blocks the regulatory
development of macrophages and leads to fatal inflammatory responses and
septic shock in mice [86]. Luiz et al. found that
CD39−/− macrophages stimulated with LPS and ATP
exhibit increased nuclear factor-kB activation and IL-1β production[87]. In another study, blocking the expression of
CD39 on the surface of macrophages enhanced the production of TNF-α and
IL-12 significantly but decreased the production of IL-10[87, 88].
ATP-based intercellular communication is mediated by P2X4R and P2X7R,
and is a feature of pro-inflammatory macrophages. It was shown that
CD39-expressing macrophages played a role in modulating the
P2X7R-dependent production of IL-1β [89]. A
previous report demonstrated that P2X7R activation triggers the
initiation of lipid raft-dependent regulatory pathways that up-regulate
CD39 activity. This mechanism could limit macrophage responses in
inflammation, hence, restoring homeostasis [90]. A
different study showed that cAMP up-regulates the transcription of CD39
in mouse macrophages, which is dependent on protein kinase A (PKA),
phosphoinositide 3-kinase (PI3K), and extracellular signal-regulated
kinase (ERK) [91].
Tumor associated macrophages (TAMs) are an important component of the
tumor microenvironment. In some cancers, TAMs can form up to 50% of
tumor tissue and seriously impair anti-tumor immunity[92]. It has been shown that macrophages were
reduced in the lungs of tumor-bearing mice treated with anti-CD39[73]. Co-culture of healthy donor monocytes with
ovarian cancer cells induced the differentiation of monocytes into
anti-inflammatory M2 macrophages expressing high levels of CD73 and
CD39. These ADO-producing TAMs were further demonstrated to inhibit
CD4+ T-cell activation in vitro[92].