ABSTRACT
Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.
Subject(s)
Ataxia Telangiectasia/immunology , DNA Damage , DNA/immunology , Listeria monocytogenes/immunology , Listeriosis/immunology , Membrane Proteins/metabolism , Animals , Ataxia Telangiectasia Mutated Proteins/genetics , Bone Marrow Cells/immunology , Cell Line , Cytosol/immunology , Cytosol/microbiology , DNA Repair/genetics , Enzyme Activation/immunology , HEK293 Cells , Humans , Immunity, Innate , Interferon-alpha/biosynthesis , Interferon-beta/biosynthesis , Interferon-gamma/biosynthesis , Macrophages/immunology , Mice , Mice, Knockout , Protein Serine-Threonine Kinases/metabolism , RNA, Small Interfering/genetics , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The remodeling of axonal circuits after injury requires the formation of new synaptic contacts to enable functional recovery. Which molecular signals initiate such axonal and synaptic reorganisation in the adult central nervous system is currently unknown. Here, we identify FGF22 as a key regulator of circuit remodeling in the injured spinal cord. We show that FGF22 is produced by spinal relay neurons, while its main receptors FGFR1 and FGFR2 are expressed by cortical projection neurons. FGF22 deficiency or the targeted deletion of FGFR1 and FGFR2 in the hindlimb motor cortex limits the formation of new synapses between corticospinal collaterals and relay neurons, delays their molecular maturation, and impedes functional recovery in a mouse model of spinal cord injury. These results establish FGF22 as a synaptogenic mediator in the adult nervous system and a crucial regulator of synapse formation and maturation during post-injury remodeling in the spinal cord.