Abstract
Generalized pustular psoriasis (GPP), the most grievous variant of psoriasis, is featured by dysregulated systemic inflammatory response. The cellular and molecular basis of GPP is poorly understood. Blood monocytes are key players of host defense and producers of inflammatory cytokines including IL-1β. How the immune response of monocytes is affected by metabolic internal environment in GPP remains unclear. Here, we performed a metabolomic and functional investigation of GPP serum and monocytes. We demonstrated a significant increase in IL-1β production from GPP monocytes. In GPP circulation, serum amyloid A (SAA), an acute-phase reactant, was dramatically increased, which induced the release of IL-1β from monocytes in a NLRP3-dependent manner. Using metabolomic analysis, we showed that GPP serum exhibited an amino acid starvation signature, with glycine, histidine, asparagine, methionine, threonine, lysine, valine, isoleucine, tryptophan, tyrosine, alanine, proline, taurine and cystathionine being markedly downregulated. In functional assay, under amino acid starvation condition, SAA-stimulated mature IL-1β secretion was suppressed. Mechanistically, at post-transcriptional level, amino acid starvation inhibited the SAA-mediated reactive oxygen species (ROS) formation and NLRP3 inflammasome activation. Moreover, the immune-modulatory effect of amino acid starvation was blocked by silencing general control nonderepressible 2 kinase (GCN2), suggesting the involvement of amino acid response (AAR) pathway. Collectively, our results suggested that decreased serum amino acids in GPP blunted the innate immune response in blood monocytes through AAR pathway, serving as a feedback mechanism preventing excessive inflammation in GPP.
Highlights
Generalized pustular psoriasis (GPP) is an uncommon and lifethreatening disease, which is featured by generalized erythema, desquamation, and dramatic cutaneous neutrophilic infiltration [1]
We demonstrated that amino acid starvation dampened NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome activation and IL-1b production induced by serum amyloid A (SAA) in monocytes
We sought to examine the mRNA level of IL-1b in human blood monocytes isolated from GPP, psoriasis vulgaris (PV) patients and healthy controls (HC)
Summary
Generalized pustular psoriasis (GPP) is an uncommon and lifethreatening disease, which is featured by generalized erythema, desquamation, and dramatic cutaneous neutrophilic infiltration [1]. IL-1 is one of the dominant cytokines in GPP autoinflammation [2, 3]. The pathological role of IL-1b in psoriasis has been reported [4, 5]. It was reported that GPP patients treated with antiIL-1b monoclonal antibodies had dramatic clinical improvement [6, 7]. As one of major producers of IL-1b, monocytes initiate and promote inflammation in the context of sterile and sterile injury, and during autoinflammatory diseases [8, 9]. It would be of critical importance to investigate the production and regulation mechanism of IL-1b in GPP
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