On one hand, we know that DNA is highly susceptible to chemical damage. The DNA replication and repair machinery, moreover, make mistakes. On the other hand, cells possess a sophisticated DNA repair system [1].
Mitochondria are particularly susceptible to DNA damage, since they act as the cellular powerhouses and have to deal with a permanent production of reactive oxygen species (ROS). It is true that an imbalance between ROS generation and cellular system’s ability for clearance, promotes damage to lipids, proteins and nucleic acids throughout the cell [2]. Mitochondrial DNA, however, besides its close contact with the respiratory chain, is not protected by histones or a nuclear envelope, becoming an easy target to oxidative lesions. Finally, it is important to cite that besides small, the mitochondrial genome encodes 13 proteins that take part in the oxidative phosphorylation complex [3] and mutations in such genes can also serve to increase ROS cellular levels. Such factors contribute to a high mutagenesis rate [3].
ROS accumulation can lead to DNA base modifications, deletions, strand breaks and crosslinks. Oxidative stress and DNA damage have been linked with multiple chronic conditions, such as cancer [4], neurodegenerative processes [5], diabetes [6], cardiovascular diseases [7, 8], chronic inflammatory diseases [9] and aging [10]. Here, we hypothesize that DNA damage may also be an important phenomenon to the pathophysiology of sepsis, an acute condition characterized by deregulation of the immune response and intense systemic inflammation. Since the brain is particularly susceptible in sepsis and mitochondrial and immune functions are tightly linked [11, 12], we decided to investigate DNA damage in the prefrontal cortex of wild-type and CRAMP-deficient mice, submitted or not to experimental sepsis.
Cathelin-derived antimicrobial peptide (CRAMP) is an antimicrobial peptide that modulates several aspects of the immune response [13]. It is the only cathelicidin in rodents and its counterpart in humans is named LL-37. Cathelicidins are a family of antimicrobial peptides able to directly kill a range of pathogens, including bacteria, protozoa and virus. Despite that, cathelicidins also play a dual role in the immune-inflammatory response through intriguing and poorly understood mechanisms. Indeed, depending on the disease and cellular context, cathelicidins can stimulate or inhibit the immune-inflammatory system [14].