Indeed, when PBMCs derived from IFN-β-treated patients were deple

Indeed, when PBMCs derived from IFN-β-treated patients were depleted of monocytes, the strong induction of IL-6 observed in total PBMCs was completely lost. In addition, a strong reduction of BAFF expression was observed in in vivo IFN-β-conditioned PBMCs after the depletion of monocytes. In a similar fashion, in the absence of monocytes, there was no induction of TLR7-driven IgM and IgG production, indicating that IFN-β treatment could exert its therapeutic effects ABT-263 in vivo by fine-tuning monocyte functions, in the context of TLR7 stimulation, that act through bystander mechanisms on the differentiation of

B lymphocytes. Taking into account that TLR7 is crucial for type I IFN release from pDC [41] and is, at the same time, an IFN-inducible gene [22], we can envisage the existence of a tight relation between IFN-β response and TLR7 responsiveness of MS monocytes, whose full comprehension deserves further investigation. In line with this view, recent data obtained by Molnarfi and collaborators showed that monocytes from RRMS patients exhibited a reduced ability to produce HGF, a neuroprotective and neuroinflammation-suppressive mediator, when compared with HD [42]. Treatment with IFN-β significantly enhanced

HGF mTOR inhibitor synthesis and secretion by blood monocytes, contributing to the clinical benefit of IFN-β in RRMS via the combined HGF-mediated neuroprotective and anti-inflammatory mechanisms. In this context, it is also important to remind that monocytes are abundant in inflammatory MS brain lesions and displayed also altered functions and an activated innate immune signature Idoxuridine in MS patients with clinically more severe course [43]. In particular,

the type I IFN pathway is dysregulated in these monocytes, which may contribute to more active disease. In addition to that, conditional genetic knockout of IFNAR1 in monocytes, but not in T cells, B cells, or central nervous system cells, leads to enhanced disease severity in the animal model of MS [44]. All these evidences indicate that perturbations of the type I IFN signaling pathway and response in monocytes could represent crucial events in MS immunopathology and, at the same time, a key target of IFN-β therapy. On the other hand, we cannot exclude that the replenished TLR7 responsiveness in PBMCs and monocytes of IFN-β-treated MS patients could be related to the rescue or prevention of TLR7 tolerance, that is generally induced by specific ligands of this receptor and leads to a reduced cytokine and Ig production [45]. Indeed, Poovassery and Bishop [45] recently demonstrated that IFN-β controls TLR7 tolerance and activation through the PI3K/Akt/mammalian target of rapamycin signaling pathway but also enhancing TLR7 expression in human B cells.

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