Juan Pablo de Rivero Vaccari, Ph.D., M.S.B.A.

Innate Immunity in CNS injury and Disease

My research focuses on understanding early inflammatory events corresponding to the innate immune response, the first line of defense against tissue damage and infections.

The immune response is divided into two phases: Innate immunity and adaptive immunity. The innate immune phase corresponds to the early events of the inflammatory response and precedes the adaptive immune phase.  It is classically defined as the first line of defense against infections and damage. It is initiated by danger/damage-associated molecular patterns (DAMPs) or by pathogen-associated molecular patterns (PAMPs) that are recognized by pattern recognition receptors (PRRs). DAMPs are endogenous ligands such as ATP, DNA or RNA, whereas PAMPs include exogenous activators like bacterial lipopolysaccharide, bacterial flagellin or viral components.

PRRs include toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs) and C-type lectin receptors (CLRs). Upon PRR-activation, there are a series of signaling events that result in the production of inflammatory cytokines such as interleukin (IL)-1b, IL-18, tumor necrosis factor (TNF) or type I interferons (IFN), among others. These cytokines contribute to tissue damage by mechanisms such as cell death and exacerbated inflammation.

INFLAMMASOMES: Of particular interest to us is the role of the inflammasome, a multiprotein complex involved in the activation of caspase-1, the formation of ASC specks, the processing of the pro-inflammatory cytokines IL-1b and IL-18, and the cell death mechanism of pyroptosis in central nervous system (CNS) injury and disease with a focus on spinal cord injury, traumatic brain injury, stroke, inflammaging, Alzheimer’s Disease and Parkinson’s Disease

BIOMARKERS: We study biomarkers as prognostic and diagnostic options that also have the  potential to be used as therapeutic targets to improve outcomes after CNS injury and disease. The development of biomarkers for CNS injury and disease has the potential to improve the care of patients by determining the severity of damage to the CNS as well as by monitoring the recovery of patients after therapeutic interventions.

My laboratory studies the innate immune response in the following conditions:

Spinal Cord Injury (SCI): Considering that many patients with SCI are young adults, and that no-FDA approved therapy is yet available, SCI is devastating. The inflammatory response is part of the secondary injury cascade of SCI events and is partially responsible for the deleterious effects occurring after trauma. Therefore, anti-inflammatory therapies offer the possibility of limiting damage after SCI; hence, resulting in improved histopathological and functional outcomes.

Traumatic Brain Injury (TBI): Traumatic brain injury is the leading cause of disability in young adults. The inflammatory response after TBI contributes to neuronal death and progressive axonal loss over days to weeks after injury; thus, a better understanding of how inflammation contributes to brain damage after injury is of utmost importance in order to develop better therapies to improve outcomes in this patient population.

Stroke: Stroke is a major problem affecting populations worldwide. It is the second most common cause of death in the world after heart disease. In the United States stroke is the fourth leading cause of death, and the societal costs are approximately 80 billion dollars, which are expected to double by the year 2030. Moreover, the inflammatory response is a key contributor to the deleterious outcomes after stroke. As a result, it is important to identify new and better anti-inflammatory therapies aimed at successfully treating this patient population.

Inflammaging, Alzheimer’s Disease (AD) and Parkinson’s Disease (PD): As we age our brain produces a basal level of inflammation that progresses over time, a phenomenon referred to as inflammaging. This inflammatory response in part contributes to the cognitive decline associated with aging, and it also contributes to the development of neurodegenerative disease like AD and PD. Thus, by therapeutically targeting the inflammatory response we have the potential to delay the onset of neurodegeneration.