posted on 2021-09-03, 18:35authored byModi Wang, Riddhi Chaudhuri, Wilson W. S. Ong, Herman O. Sintim
Many
pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide
(LPS) and lipoteichoic acid, are potent immunostimulatory molecules
and promote the expression of cyclooxygenase 2 (COX-2). While the
production of COX-2, and ultimately prostaglandin E2, could
be protective, persistent induction of COX-2 leads to inflamed environments
that can result in septic shock and death. Bacterial derived cyclic
dinucleotides (CDNs), c-di-GMP and c-di-AMP, are also PAMPs and have
been shown to produce inflamed environments via the production of
pro-inflammatory cytokines such as type I interferons. The well-characterized
CDN immunostimulatory mechanism involves binding to stimulator of
interferon genes (STING), which ultimately results in the phosphorylation
of IRF3 or release of NF-κB to promote expression of type I
IFN or pro-inflammatory cytokines. In this study, we sought to investigate
if CDNs promote COX-2 expression. Using RAW macrophages as a model
system, we reveal that c-di-GMP, but not c-di-AMP or the host-derived
2′,3′-cGAMP, promotes COX-2 expression. Using analogues
of CDNs, we show that the presence of two guanines and two 3′,5′-phosphodiester
linkages are requirements for the promotion of COX-2 expression by
cyclic dinucleotides. Both c-di-GMP and LPS inductions of COX-2 expression
in RAW macrophages are STING-independent and are regulated by Tpl2-MEK-ERK-CREB
signaling; inhibitors of Tpl2, MEK, and ERK could attenuate COX-2
expression promoted by c-di-GMP. This work adds to the growing body
of evidence that cyclic dinucleotides regulate pathways other than
the STING–TBK1–IRF3 axis. Additionally, the differential
COX-2 induction by c-di-GMP but not c-di-AMP or cGAMP suggests that
the type and level of inflammation could be dictated by the nucleotide
signature of the invading pathogen.