Titolo della tesi: Trained immunity induced by muscle injury: a focus on inflammatory monocytes
This PhD project investigates the induction of trained immunity in
innate immune cells, such as inflammatory Ly6Chi monocytes in
the context of skeletal muscle injury. Trained immunity (TI) is a
type of non-specific memory induced in monocytes following
exposure to pathogen or damage associated signals, leading to
elevated production of cytokines upon secondary stimulation. This
work is focused on understanding whether and how this
phenomenon occurs after muscle injury, and what impact it has on
muscle repair. Using mouse models of acute (CTX) and chronic
(Duchenne muscular dystrophy (DMD)) muscle injury, splenic and
bone marrow monocytes were analysed for cytokine production
and other hallmarks of trained immunity induction.
The findings reveal that, TI is a feature of both acute and chronic
muscle injury as evidenced by amplified cytokine and chemokine
responses in monocytes following LPS stimulation in vitro.
Interestingly, TI induced after acute muscle injury, seems to
enhance myogenesis, as satellite cells exposed to factors released
by trained monocytes proliferate more and form bigger myotubes.
However, in the context of chronic muscle injury such as in DMD,
chronic stimulation of TI leads to excessive and/or dysregulated
cytokine production that may contribute to persistent inflammation
and fibrosis. Indeed, targeting trained immunity in DMD mice with
mTORi-nanobiologics helped to rebalance pro- and anti-
inflammatory cytokine production by trained monocytes resulting
in improved muscle regeneration and reduced fibrosis. Altogether,
these results suggest that while TI induced by acute muscle injury
might be beneficial in promoting muscle repair, it is detrimental in
chronic degenerative conditions, and its targeted inhibition may
represent a promising novel therapeutic strategy to restore muscle
homeostasis in DMD.