VEGF-A from Granuloma Macrophages Regulates Granulomatous Inflammation by a Non-angiogenic Pathway during Mycobacterial Infection.

Many autoimmune and infectious diseases are characterized by the formation of granulomas which are inflammatory lesions that consist of spatially organized immune cells. These sites protect the host and control pathogens like Mycobacterium tuberculosis (Mtb), but are highly inflammatory and cause pathology. Using bacille Calmette-Guerin (BCG) and Mtb infection in mice that induce sarcoid or caseating granulomas, we show that a subpopulation of granuloma macrophages produces vascular endothelial growth factor (VEGF-A), which recruits immune cells to the granuloma by a non-angiogenic pathway. Selective blockade of VEGF-A in myeloid cells, combined with granuloma transplantation, shows that granuloma VEGF-A regulates granulomatous inflammation. The severity of granuloma-related inflammation can be ameliorated by pharmaceutical or genetic inhibition of VEGF-A, which improves survival of mice infected with virulent Mtb without altering host protection. These data show that VEGF-A inhibitors could be used as a host-directed therapy against granulomatous diseases like tuberculosis and sarcoidosis, thereby expanding the value of already existing and approved anti-VEGF-A drugs.

Neuroprotection in Oxidative Stress-Related Neurodegenerative Diseases: Role of Endocannabinoid System Modulation.

SIGNIFICANCE: Redox imbalance may lead to overproduction of reactive oxygen and nitrogen species (ROS/RNS) and subsequent oxidative tissue damage, which is a critical event in the course of neurodegenerative diseases. It is still not fully elucidated, however, whether oxidative stress is the primary trigger or a consequence in the process of neurodegeneration. Recent Advances: Increasing evidence suggests that oxidative stress is involved in the propagation of neuronal injury and consequent inflammatory response, which in concert promote development of pathological alterations characteristic of most common neurodegenerative diseases. CRITICAL ISSUES: Accumulating recent evidence also suggests that there is an important interplay between the lipid endocannabinoid system [ECS; comprising the main cannabinoid 1 and 2 receptors (CB1 and CB2), endocannabinoids, and their synthetic and metabolizing enzymes] and various key inflammatory and redox-dependent processes. FUTURE DIRECTIONS: Targeting the ECS to modulate redox state-dependent cell death and to decrease consequent or preceding inflammatory response holds therapeutic potential in a multitude of oxidative stress-related acute or chronic neurodegenerative disorders from stroke and traumatic brain injury to Alzheimer's and Parkinson's diseases and multiple sclerosis, just to name a few, which will be discussed in this overview. Antioxid. Redox Signal. 29, 75-108.