Inflammasomes are multiprotein complexes that respond to pathogen-associated or damage-associated molecular patterns (PAMPs or DAMPs), which results in the processing of pro-interleukin-1β (pro-IL-1β) and pro-IL-18, secretion of the mature forms of these proinflammatory cytokines, and pyroptotic cell death. First, PAMPs, such as lipopolysaccharide (LPS), induce expression of the genes encoding the pro forms of IL-1β and IL-18. Second, detection of PAMPs or DAMPs by a pattern-recognition receptor, such as NLRP3, results in inflammasome assembly, caspase-1 activation, and cytokine processing. The second messenger cyclic adenosine monophosphate (cAMP)—which is generated in response to signaling by a subset of G protein–coupled receptors (GPCRs), including the prostaglandin E2 (PGE2) receptor EP4—is thought to bind to NLRP3, targeting it for ubiquitylation and degradation, thus preventing inflammasome assembly. Mortimer et al. found that PGE2 inhibited NLRP3 inflammasome activity and cytokine secretion by macrophages treated with both LPS and nigericin (a stimulator of NLRP3 inflammasome assembly). This inhibitory effect of PGE2 was mediated by EP4 and was blocked by an antagonist of cAMP-dependent protein kinase (PKA). PKA directly phosphorylated NLRP3 at Ser295 in vitro, which inhibited the ATPase activity of NLRP3, an activity that is required for inflammasome assembly. In transfected cells, cAMP failed to inhibit the activity of a S295A mutant NLRP3 protein. Cryopyrin-associated periodic syndrome (CAPS) refers to a family of inflammatory disorders characterized by aberrant activity of the NLRP3 inflammasome. Mutational studies showed that some of the mutations associated with CAPS occur in residues near Ser295 of NLRP3. In six out of seven cases, cAMP failed to inhibit NLRP3 inflammasome activity in cells expressing CAPS-related mutant NLRP3 proteins. As Swanson and Ting discuss, these findings suggest that in addition to inhibiting NLRP3 inflammasome assembly, cAMP also shuts down active NRLP3 signaling through PKA to restrain inflammation.
L. Mortimer, F. Moreau, J. A. MacDonald, K. Chadee, NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations. Nat. Immunol. 17, 1176–1186 (2016). [PubMed]
K. V. Swanson, J. P.-Y. Ting, Reining in uncontrolled inflammasome with PKA. Nat. Immunol. 17, 1137–1138 (2016). [PubMed]