Differential neutrophil infiltration contributes to regional differences in brain inflammation in the substantia nigra pars compacta and cortex

Abstract

Brain inflammation is a suggested risk factor for neurodegenerative disease. Interestingly, severe inflammation in the substantia nigra pars compacta (SNpc) accelerates the onset and progression of Parkinson's disease. In this study, we examined the underlying mechanisms of severe inflammation in the SNpc by comparing the inflammatory process with that in the cortex. In intact brain, the densities of CD11b 1 microglia were similar in the SNpc and cortex. However, lipopolysaccharide injection enhanced the CD11b 1 cell number in the SNpc, but not in the cortex. Previously, we reported that CD11b and myeloperoxidase (MPO) double-positive neutrophils infiltrate the SNpc following LPS injection (GLIA 55:1577-88). Notably, the MPO 1 neutrophil number increased dramatically in the SNpc, but only slightly in the cortex. The extent of neutrophil infiltration appeared to correlate with neuronal damage. We confirmed that loss of neurons in the SNpc was significantly reduced in neutropenic rats versus normal rats following LPS injection. In addition, the densities of astrocytes were much lower in the intact SNpc, compared with the cortex. Furthermore, after LPS injection, damage of endothelial cells and astrocytes, and blood-brain barrier (BBB) permeability was more pronounced in the SNpc. These results collectively suggest that excessive neutrophil infiltration and environmental factors, such as lower astrocyte density and higher BBB permeability, contribute to severe inflammation and neuronal death in the SNpc. V V C

Systemic LPS administration induces brain inflammation but not dopaminergic neuronal death in the substantia nigra

“…Neutrophils are a major source of proinflammatory mediators including iNOS, Cyclooxygenase-2, Monocyte chemotactic protein-1, which play important roles in neuronal death within LPS-injected and/or ischemic brains (Ji et al, 2007;Matsumoto et al, 2007). Previously, we found that direct injection of LPS recruited more neutrophils to the SN than to the cortex or hippocampus, which suggests that susceptibility to LPS neurotoxicity may differ among these regions (Figure 2B LPS SN; Ji et al, 2008). LPS iv injection recruited fewer neutrophils than did direct LPS injection ( Figure 2B), and induced only transient expression of inflammatory mediators, lasting for up to 1-3 d (Figure 1-3).…”

Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

“…Indeed, BBB leakage has been observed in PD patients [344] as well as in animal models of PD [345,346]. Interestingly, the substantia nigra region is reportedly more prone to BBB disruption and neutrophil infiltration than is the cortical region [347].…”

Uridine 5′-Diphosphate Induces Chemokine Expression in Microglia and Astrocytes through Activation of the P2Y6 Receptor

“…Chemokines are implicated in the pathogenesis of a number of neurologic diseases, including Alzheimer's disease, cerebral ischemia, and multiple sclerosis (4). Chemokines are major effector molecules recruiting blood inflammatory cells to the injury site (5), and recently, several studies have reported that blood inflammatory cells also enter the injured brain and participate in brain inflammation (6)(7)(8). In particular, CCL2 (MCP-1) and CCL3 (MIP-1a) are important chemokines associated with monocyte infiltration into the injured brain (9)(10)(11)(12).…”