Abstract
Background:
Lipopolysaccharide (LPS) produced by Gram-negative bacteria effectively
stimulates the maturation of bone marrow (BM)-derived dendritic cells
(BMDCs). Previous studies have shown that LPS-activated BMDCs (DClps)
might induce tolerance in autoimmune diseases and cancer in vivo,
whereas it remains unclear whether DClps can modulate the immune
microenvironment in allergic asthma.
Objectives: We sought to elucidate the potential effects of DClps on
OVA-sensitized/challenged airway inflammation in a mouse model of
asthma, which may help facilitate the application of specific
tolerogenic dendritic cells (tolDCs) in allergic asthma patients in the
future.
Methods: We generated and obtained DClps from wild-type mice to evaluate
their functional characteristics by ELISA and FACS. We also induced
OVA-sensitized/challenged asthmatic mice and intraperitoneally treated
these mice with DClps to assess the effects of these injected cells by
histopathologic analysis and performing inflammatory cell counts in
bronchoalveolar lavage fluid (BALF). Changes in memory CD4+ T cells,
regulatory T cells (Tregs) and phosphorylated protein in lung digests
were analyzed.
Results: DClps exhibited lower levels of CD80
and
MHC class II molecules (MHCII) and increased levels of anti-inflammatory
cytokines such as IL-10 and TGF-β than immature DCs (DCia).
Additionally, DClps treatment dramatically ameliorated airway
inflammation and diminished the infiltration of pulmonary inflammatory
cells. In addition, we prolonged the modeling time of asthmatic mice and
demonstrated that DClps treatment decreased the proliferation activity
of pulmonary memory CD4+ T cells, which further rendered the
downregulation of type 2 T helper (Th2) cytokines. However, the number
of pulmonary Tregs did not discernibly change. DClps treatment also
markedly reduced the phosphorylation level of STAT6 protein.
Conclusion: Our findings demonstrate that LPS stimulation may lead to a
tolerogenic phenotype in BMDCs, which can induce tolerance and regulate
the microenvironment of asthmatic mice, possibly through the
upregulation of anti-inflammatory cytokines, inhibition of pulmonary
memory CD4+ T cells and downregulation of STAT6 phosphorylation.