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The secreted protein, YKL-40, has been proposed as a biomarker of a variety of human diseases characterized by ongoing inflammation, including chronic neurological pathologies such as multiple sclerosis (MS)2 and Alzheimer’s disease. However, inflammatory mediators and the molecular mechanism responsible for enhanced expression of YKL-40 remained elusive. Using several mouse models of inflammation, we now show that YKL-40 expression correlated with increased expression of both IL-1 and IL-6. Furthermore, IL-1 together with IL-6 or the IL-6 family cytokine, oncostatin M (OSM), synergistically upregulated YKL-40 expression in both primary human and mouse astrocytes in vitro. The robust cytokine-driven expression of YKL-40 in astrocytes required both STAT3 and NF-κB binding elements of the YKL-40 promoter. Additionally, YKL-40 expression was enhanced by constitutively active STAT3 and inhibited by dominant-negative IκBα. Surprisingly, cytokine-driven expression of YKL-40 in astrocytes was independent of the p65 subunit of NF-κB and instead required subunits RelB and p50. Mechanistically, we show that IL-1-induced RelB/p50 complex formation was further promoted by OSM and that these complexes directly bound to the YKL-40 promoter. Moreover, we found that expression of RelB was strongly upregulated during inflammation in vivo and by IL-1 in astrocytes in vitro. We propose that IL-1 and the IL-6 family of cytokines regulate YKL-40 expression during sterile inflammation via both STAT3 and RelB/p50 complexes. These results suggest that IL-1 may regulate the expression of specific anti-inflammatory genes in non-lymphoid tissues via the canonical activation of the RelB/p50 complexes.

In response to brain injury or infections, astrocytes become reactive, undergo striking morphological and functional changes, and secrete and respond to a spectrum of inflammatory mediators. We asked whether reactive astrocytes also display adaptive responses during sterile IL‐1β‐induced neuroinflammation, which may limit tissue injury associated with many disorders of the central nervous system. We found that astrocytes display days‐to‐weeks long specific tolerance of cytokine genes, which is coordinated by NF‐κB family member, RelB. However, in contrast to innate immune cells, astrocytic tolerance does not involve epigenetic silencing of the cytokine genes. Establishment of tolerance depends on persistent higher levels of RelB in tolerant astrocytes and its phosphorylation on serine 472. Mechanistically, this phosphorylation prevents efficient removal of RelB from cytokine promoters by IκBα and helps to establish tolerance. Importantly, ablation of RelB from astrocytes in mice abolishes tolerance during experimental neuroinflammation in vivo.

Glioblastoma multiforme (GBM) is a primary brain tumor characterized by extensive necrosis and immunosuppressive inflammation. The mechanisms by which this inflammation develops and persists in GBM remain elusive. We identified two cytokines interleukin-1β (IL-1) and oncostatin M (OSM) that strongly negatively correlate with patient survival. We found that these cytokines activate RelB/p50 complexes by a canonical NF-κB pathway, which surprisingly drives expression of proinflammatory cytokines in GBM cells, but leads to their inhibition in non-transformed astrocytes. We discovered that one allele of the gene encoding deacetylase Sirtuin 1 (SIRT1), needed for repression of cytokine genes, is deleted in 80% of GBM tumors. Furthermore, RelB specifically interacts with a transcription factor Yin Yang 1 (YY1) in GBM cells and activates GBM-specific gene expression programs. As a result, GBM cells continuously secrete proinflammatory cytokines and factors attracting/activating glioma-associated microglia/macrophages and thus, promote a feedforward inflammatory loop.

Pattern recognition receptors (PRRs) coordinate the innate immune response and have a significant role in the development of multiple sclerosis (MS). Accumulating evidence has identified both pathogenic and protective functions of PRR signaling in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Additionally, evidence for PRR signaling in non-immune cells and PRR responses to host-derived endogenous ligands has also revealed new pathways controlling the development of CNS autoimmunity. Many PRRs remain uncharacterized in MS and EAE, and understanding the distinct triggers and functions of PRR signaling in CNS autoimmunity requires further investigation. In this brief review, we discuss the diverse pathogenic and protective functions of PRRs in MS and EAE, and highlight major avenues for future research.

The neuroinflammation associated with multiple sclerosis involves activation of astrocytes that secrete and respond to inflammatory mediators such as IL-1. IL-1 stimulates expression of many chemokines, including C-C motif ligand (CCL) 5, that recruit immune cells, but it also stimulates sphingosine kinase-1, an enzyme that generates sphingosine-1-phosphate (S1P), a bioactive lipid mediator essential for inflammation. We found that whereas S1P promotes IL-1-induced expression of IL-6, it inhibits IL-1-induced CCL5 expression in astrocytes. This inhibition is mediated by the S1P receptor (S1PR)-2 via an inhibitory G-dependent mechanism. Consistent with this surprising finding, infiltration of macrophages into sites of inflammation increased significantly in S1PR2(-/-) animals. However, activation of NF-κB, IFN regulatory factor-1, and MAPKs, all of which regulate CCL5 expression in response to IL-1, was not diminished by the S1P in astrocytes. Instead, S1PR2 stimulated inositol 1,4,5-trisphosphate-dependent Ca(++) release and Elk-1 phosphorylation and enhanced c-Fos expression. In our study, IL-1 induced the IFNβ production that supports CCL5 expression. An intriguing finding was that S1P induced c-Fos-inhibited CCL5 directly and also indirectly through inhibition of the IFN-β amplification loop. We propose that in addition to S1PR1, which promotes inflammation, S1PR2 mediates opposing inhibitory functions that limit CCL5 expression and diminish the recruitment of immune cells.

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Background Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). It is firmly established that overactivation of the p65 (RelA) nuclear factor kappa B (NF-κB) transcription factor upregulates expression of inflammatory mediators in both immune and non-immune resident CNS cells and promotes inflammation during MS. In contrast to p65, NF-κB family member RelB regulates immune cell development and can limit inflammation. Although RelB expression is induced during inflammation in the CNS, its role in MS remains unknown. Methods To examine the role of RelB in non-immune CNS cells, we generated mice with RelB specifically deleted in astrocytes (RelB ΔAST ), oligodendrocytes (RelB ΔOLIGO ), or neural progenitor-derived cells (RelB ΔNP ). We used experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS, to assess the effect of RelB deletion on disease outcomes and performed analysis on the histological, cellular, and molecular level. Results Despite being a negative regulator of inflammation, conditional knockout of RelB in non-immune resident CNS cells surprisingly decreased the severity of EAE. This protective effect was recapitulated by conditional deletion of RelB in oligodendrocytes but not astrocytes. Deletion of RelB in oligodendrocytes reduced disease severity, promoted survival of mature oligodendrocytes, and correlated with increased activation of p65 NF-κB. Conclusions These findings suggest that RelB fine tunes inflammation and cell death/survival during EAE. Importantly, our data points out the detrimental role RelB plays in controlling survival of mature oligodendrocytes, which could be explored as a viable option to treat MS in the future. Electronic supplementary material The online version of this article (10.1186/s12974-019-1548-7) contains supplementary material, which is available to authorized users.