Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm

The circulatory and migratory properties of white blood cells have evolved to allow efficient surveillance of tissues for infectious pathogens and rapid accu­ mulation at sites of injury and infection. Lymphocytes continually patrol the body for foreign antigen by recirculating from blood, through tissue, into lymph, and back to blood. Lymphocytes acquire a predilection, based on the environment in which they first encounter foreign antigen, to home to or recirculate through that same environment (39, 40). Granulocytes and mono­ cytes cannot recirculate, but emigrate from the bloodstream in response to molecular changes on the surface of blood vessels that signal injury or infec­ tion. Lymphocytes can similarly accumulate in response to inflammatory stim­ uli. The nature of the inflammatory stimulus determines whether lymphocytes. monocytes, neutrophils, or eosinophils predominate, and thus exercises spec­ ificity in the molecular signals or "area codes" that are displayed on endothe­ lium and control traffic of particular leukocyte classes. Recent findings show that the "traffic signals" for lymphocyte recirculation and for neutrophil and monocyte localization in inflammation are strikingly similar at the molecular level. These traffic signal or area code molecules are

Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration

Selectins and their ligands: current concepts and controversies.

Lymph nodes (LNs) are the organs where innate immune responses lead to acquired immunity, where some of our most devastating pathogens evade immunity, and where autoreactive lymphocytes first encounter tissue-specific self-antigens and are either tolerized or activated. The many roles of LNs depend on the coordinated migration of its cellular constituents. This article covers new insights into the organization and microvascular specialization of LNs, the guidance mechanisms that allow lymphocytes and antigen-presenting cells to find their correct place in the nodal parenchyma; and the role of afferent lymph flow in LN function.

Homing and cellular traffic in lymph nodes

Lymphangiogenesis: Molecular Mechanisms and Future Promise

Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Neuroinflammation is linked to the accumulation and aggregation of a-synuclein (αSyn), the primary pathological hallmark of PD. Toll-like receptors 4 (TLR4) can have implications in the development and progression of the pathology. In this study, we analyzed the expression of TLR4 in the substantia nigra (SN) and medial temporal gyrus (GTM) of well-characterized PD patients and age-matched controls. We also assessed the co-localization of TLR4 with pSer129 αSyn. Using qPCR, we observed an upregulation of TLR4 expression in the SN and GTM in PD patients compared to controls, which was accompanied by a reduction in αSyn expression likely due to the depletion of dopaminergic (DA) cells. Additionally, using immunofluorescence and confocal microscopy, we observed TLR4-positive staining and co-localization with pSer129-αSyn in Lewy bodies of DA neurons in the SN, as well as in pyramidal neurons in the GTM of PD donors. Furthermore, we observed a co-localization of TLR4 and Iba-1 in glial cells of both SN and GTM. Our findings provide evidence for the increased expression of TLR4 in the PD brain and suggest that the interaction between TLR4 and pSer129-αSyn could play a role in mediating the neuroinflammatory response in PD.

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Toll-like Receptor 4 Is Upregulated in Parkinson’s Disease Patients and Co-Localizes with pSer129αSyn: A Possible Link with the Pathology

Transcription factor EB is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis of GBA-related and sporadic Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). TFEB activation at the lysosomal level results in its translocation from the cytosol to the nucleus. Here, we aimed at investigating whether TFEB subcellular localization is altered in post-mortem human brain of aged individuals with either prodromal PD/DLB (incidental Lewy body disease, iLBD, N=3), GBA-related PD/DLB (N=9) or sPD/DLB (N=9), compared to control subjects (N=12). We scanned nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the observed TFEB subcellular localization patterns. In line with previous studies, we observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both sporadic and GBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn cytopathology and in cases carrying pathogenic GBA variants. Interestingly, we further observed previously unidentified TFEB-immunopositive somatic clusters in human brain dopaminergic neurons and in human embryonic stem cell (hESC)-derived neurons, which localized at the Golgi apparatus. The TFEB clustering was more frequently observed and more severe in iLBD, sPD/DLB and GBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons but also in neurons without apparent cytopathology. Notably, increased frequency of cytoplasmic TFEB clusters in aSyn-negative cells correlated with reduced total GBA enzymatic activity and higher Braak LB stage. In the studied patient population, altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected CLEAR genes, indicating a possible early dysfunction of lysosomal regulation. Overall, these findings suggest the early cytoplasmic TFEB retention and accumulation at the Golgi prior pSer129 aSyn accumulation in incidental, GBA-related and sporadic PD/DLB and indicate TFEB as potential as early therapeutic target for synucleinopathies

Altered TFEB subcellular localization in nigral dopaminergic neurons of subjects with prodromal, sporadic and GBA-related Parkinson’s disease and Dementia with Lewy bodies

John J. P. Brevé

Papers

Toll-like Receptor 4 Is Upregulated in Parkinson’s Disease Patients and Co-Localizes with pSer129αSyn: A Possible Link with the Pathology

Altered TFEB subcellular localization in nigral dopaminergic neurons of subjects with prodromal, sporadic and GBA-related Parkinson’s disease and Dementia with Lewy bodies