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positive regulators and act as an accelerator. There is increasing evidence that TLR4
and miRNA crosstalk ensures the ne-tuning of inammatory response and subse-
quent healing occurring in tissues after infection or injury. The expression of miR-
NAs inside the cell, after TLR4 triggering, critically contributes both to the activation
and to the shutdown of immune cell response needed for the termination of the
inammatory process. M.Molteni and C.Rossetti gave insight into the intracellular
role of TLR4-miRNA axis in the regulation of inammatory and anti-inammatory
processes.
Interestingly, TLR4 does not only play a role in inducing inammation but also
in inducing tissue regeneration and healing after inammatory insult, and it main-
tains homeostasis in the gut and a state of constant “controlled inammation” due
to the stimulation by commensal bacteria. When there is an imbalance of gut micro-
ora, inammatory bowel diseases can develop.
This dual role of TLR4 signaling is particularly critical in CNS, as discussed by
L.De Filippis and F.Peri. TLR4 is expressed in microglia, which is a master player
in neuroinammatory processes, as well as in neural cells: astrocytes, neurons, oli-
godendrocytes, neural progenitors (NPC), and neural stem cells (NSC). We have
observed that TLR4 stimulation by LPS during differentiation enhances neurono-
genic potential of human NSC and favors both neuronal and oligodendroglial sur-
vival. Consistent with our data, it has been recently reported that endogenous NSC
are actively stimulated to proliferate by TLR4 activation after stroke, thus conrm-
ing the relevant role of TLR4in promoting neurogenesis under non-physiological
conditions. Altogether, these results indicate that in a therapeutic perspective, TLR4
activity should not to be turned on or off, but should be nely tuned in order to pro-
mote neuroregeneration rather than neurodegeneration and to mediate the develop-
ment of healing immunomodulation rather than of detrimental neuroinammation.
Recent insight on the role of TLR4 as mediator of inammatory response in
Alzheimer’s (AD) and Parkinson’s disease (PD) has been reviewed by C.Balducci
and G.Forloni. They reported literature data relating activation of TLR4 and the
presence of β amyloid and their own data showing that the memory damage and
inammatory effects obtained by intraventricular application of β amyloid oligo-
mers was antagonized by TLR4 inhibitor and completely abolished in TLR4-
knockout mice. They also discuss the recently discovered role of TLR4 in the
relationship between gut microbiota dysbiosis and increased risk of developing PD.
M.De Paola presented new data on the potential of Human Induced Pluripotent
Stem Cells (IPSC) and Cerebral Organoids as models to study how TLR4 regulates
immune cell interactions to orchestrate brain development and reaction to injury. He
showed how the development of platforms in which microglia, neurons, and mac-
roglia derived from healthy or diseased subjects grow and mature in a single system
allows to demonstrate the role of TLR4in mediating neuroinammation.
We thank all authors, that are also our good friends, for having accepted the chal-
lenge to compose this multidisciplinary mosaic around TLR4 functions. Their dif-
ferent expertise in the elds of structural biology, biophysics, medicinal chemistry,
Preface