Immunoinflammatory diseases of the central nervous system - the tale of two cytokines.

Cytokines are potent mediators of cellular communication that have crucial roles in the regulation of innate and adaptive immunoinflammatory responses. Clear evidence has emerged in recent years that the dysregulated production of cytokines may in itself be causative in the pathogenesis of certain immunoinflammatory disorders. Here we review current evidence for the involvement of two different cytokines, IFN-α and IL-6, as principal mediators of specific immunoinflammatory disorders of the CNS. IFN-α belongs to the type I IFN family and is causally linked to the development of inflammatory encephalopathy exemplified by the genetic disorder, Aicardi-Goutières syndrome. IL-6 belongs to the gp130 family of cytokines and is causally linked to a number of immunoinflammatory disorders of the CNS including neuromyelitis optica, idiopathic transverse myelitis and genetically linked autoinflammatory neurological disease. In addition to clinical evidence, experimental studies, particularly in genetically engineered mouse models with astrocyte-targeted, CNS-restricted production of IFN-α or IL-6 replicate many of the cardinal neuropathological features of these human cytokine-linked immunoinflammatory neurological disorders giving crucial evidence for a direct causative role of these cytokines and providing further rationale for the therapeutic targeting of these cytokines in neurological diseases where indicated.

Transcription factor c-Rel plays a crucial role in driving anti-CD40-mediated innate colitis.

Genetic and environmental factors, including the commensal microbiota, have a crucial role in the development of inflammatory bowel disease. Aberrant activation of the transcription factor NF-κB is associated with chronic intestinal inflammation in mice and humans. Recently, an emerging family of innate lymphoid cells (ILCs) has been identified at mucosal sites contributing to the maintenance of gut homeostasis and intestinal immunopathology. Here, we show that the NF-κB protein c-Rel regulates the inflammatory potential of colonic IFN-γ(+)Thy1(+) ILCs to induce anti-CD40-mediated colitis in rag1(-/-) mice. Stimulation of dendritic cells (DCs) with anti-CD40 or CD40L led to translocation of c-Rel into the nucleus resulting in induction of expression of interleukin-12 (IL-12) and IL-23, key regulators of innate cell-induced colitis. While c-Rel deficiency completely abrogated anti-CD40-induced colitis, adoptively transferred wild-type DCs were able to induce pronounced colonic inflammation in rag1(-/-)rel(-/-) mice. In summary, these results suggest that the expression of c-Rel in DCs is essential for initiating anti-CD40-mediated intestinal pathogenesis.

Review: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity--a tale of conflict and conundrum.

The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity - a tale of conflict and conundrum The chemokines CXCL9, CXCL10 and CXCL11 (also known as monokine induced by interferon-gamma, interferon-inducible protein-10 and interferon-inducible T cell alpha-chemoattractant, respectively) are structurally and functionally related molecules within the non-ELR CXC chemokine subgroup. These chemokines are generally not detectable in most non-lymphoid tissues under physiological conditions but are strongly induced by cytokines, particularly interferon-gamma, during infection, injury or immunoinflammatory responses. CXCL9, CXCL10 and CXCL11 each bind to a common primary receptor, CXCR3, and possibly to additional receptors. They are best known for their role in leucocyte trafficking, principally acting on activated CD4+ Th1 cells, CD8+ T cells and NK cells. An abundance of data demonstrates that CXCL9, CXCL10 and CXCL11 are produced in many diverse pathologic conditions of the central nervous system. More recent attention has focussed on the function of these chemokines in the central nervous system inflammation. The results of these studies have proven to be sometimes surprising and other times contradictory. Here we discuss the likely more subtle and perhaps divergent roles for these chemokines in the pathogenesis of neuroinflammatory diseases.