A Pro-Inflammatory Signature Constitutively Activated in Monogenic Autoinflammatory Diseases

Abstract

Autoinflammatory diseases (AIDs) are disorders characterised by recurrent inflammatory episodes in charge of different organs with no apparent involvement of autoantibodies or antigen-specific T lymphocytes. Few common clinical features have been identified among all monogenic AIDs (mAIDs), while the search for a common molecular pattern is still ongoing. The aim of this study was to increase knowledge on the inflammatory pathways in the development of mAIDs in order to identify possible predictive or diagnostic biomarkers for each disease and to develop future preventive and therapeutic strategies. Using protein array-based systems, we evaluated two signalling pathways known to be involved in inflammation and a wide range of inflammatory mediators (pro-inflammatory cytokines and chemokines) in a cohort of 23 patients affected by different mAIDs, as FMF, TRAPS, MKD, Blau syndrome (BS), and NLRP12D. Overall, we observed upregulation of multiple signalling pathway intermediates at protein levels in mAIDs patients’ PBMCs, compared with healthy controls, with significant differences also between patients. FMF, TRAPS, and BS presented also peculiar activations of inflammatory pathways that can distinguish them. MAPK pathway activation, however, seems to be a common feature. The serum level of cytokines and chemokines produced clear differences between patients with distinct diseases, which can help distinguish each autoinflammatory disease. The FMF cytokine production profile appears broader than that of TRAPS, which, in turn, has higher cytokine levels than BS. Our findings suggest an ongoing subclinical inflammation related to the abnormal and constitutive signalling pathways and define an elevated inflammatory cytokine signature. Moreover, the upregulation of Th17-related cytokines emphasises the important role for Th17 and/or Th17-like cells also in monogenic AIDs.

Efficacy and safety of thalidomide in children with monogenic autoinflammatory diseases: a single-center, real-world-evidence study

“…The efficacy of thalidomide in Blau syndrome was 50% in this study (Fig. 2 D), suggesting that more extensive inflammatory pathways or cytokines may be involved in the mechanism of Blau syndrome [ 22 ]. In addition, our cohort reported the efficacy of thalidomide after 1 year treatment of AGS, SAVI and TRAPS in clinical practice firstly [ 23 ].…”

Polygonatum Polysaccharide Regulates Macrophage Polarization and Improves LPS-Induced Acute Lung Injury through TLR4-MAPK/NF-κB Pathway

“…Studies have found that NF- κ B signaling pathway inhibition could promote the polarization of M2 macrophages and stimulate the activation of NF- κ B showing contrary effects [ 27 ]. In addition, MAPK is known to be a threonine/serine kinase that played a key role in inflammation by regulating NF- κ B-dependent gene transcription [ 28 ]. Previous studies have found that glucosamine might play an anti-inflammatory role by inhibiting the phosphorylation of MAPK protein which hinders the M1 polarization of local macrophages [ 29 ].…”

Peripheral T cell populations are differentially affected in monogenic autoinflammatory syndromes and gout

“…While IL-1b potentiates responses of CD8 and various CD4 T cell lineages (19,21,23) it is mainly known to promote Th17 responses (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) as well as to induce IL-17producing gd T cells in mice (39). Interestingly, many autoinflammatory conditions, including FMF and gout, display upregulation of Th17-related cytokines (40)(41)(42). Not only IL-1b affects T cell responses, recent studies have shown that CD8 and CD4 T cells can in turn modulate the production of IL-1b in myeloid cells (43)(44)(45).…”