Interleukin-4 Protects Dopaminergic Neurons In vitro but Is Dispensable for MPTP-Induced Neurodegeneration In vivo

Microglia are involved in physiological as well as neuropathological processes in the central nervous system (CNS). Their functional states are often referred to as M1-like and M2-like activation, and are believed to contribute to neuroinflammation-mediated neurodegeneration or neuroprotection, respectively. Parkinson’s disease (PD) is one the most common neurodegenerative disease and is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra resulting in bradykinesia, tremor, and rigidity. Interleukin 4 (IL4)-mediated M2-like activation of microglia, which is characterized by upregulation of alternative markers Arginase 1 (Arg1) and Chitinase 3 like 3 (Ym1) has been well studied in vitro but the role of endogenous IL4 during CNS pathologies in vivo is not well understood. Interestingly, microglia activation by IL4 has been described to promote neuroprotective and neurorestorative effects, which might be important to slow the progression of neurodegenerative diseases. In the present study, we addressed the role of endogenous and exogenous IL4 during MPP+-induced degeneration of mDA neurons in vitro and further addressed the impact of IL4-deficiency on neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD in vivo. Our results clearly demonstrate that exogenous IL4 is important to protect mDA neurons in vitro, but endogenous IL4 seems to be dispensable for development and maintenance of the nigrostriatal system as well as MPTP-induced loss of TH+ neurons in vivo. These results underline the importance of IL4 in promoting a neuroprotective microglia activation state and strengthen the therapeutic potential of exogenous IL4 for protection of mDA neurons in PD models

IGF-1 Gene Therapy Modifies Inflammatory Environment and Gene Expression in the Caudate-Putamen of Aged Female Rat Brain

Brain aging is characterized by chronic neuroinflammation caused by activation of glial cells, mainly microglia, leading to alterations in homeostasis of the central nervous system. Microglial cells are constantly surveying their environment to detect and respond to diverse signals. During aging, microglia undergo a process of senescence, characterized by loss of ramifications, spheroid formation, and fragmented processes, among other abnormalities. Therefore, the study of microglia senescence is of great relevance to understand age‐related declines in cognitive and motor function.We have targeted the deleterious effects of aging by implementing gene therapy with IGF-1, employing recombinant adenoviral vectors (RAds) as a delivery system. In this study, we performed intracerebroventricular (ICV) IGF-1 gene therapy on aged female rats and evaluated its effect on Caudate-Putamen unit (CPu) gene expression and inflammatory state. IGF-1 gene therapy modified senescent microglia of the CPu towards an anti-inflammatory state increasing the proportion of Iba1+Arg1+ cells. Moreover, IGF-1 gene therapy was able to regulate the pro-inflammatory environment of CPu in female aged rats by down-regulating the expression of genes typically over-expressed during aging. Our results demonstrate that, ICV IGF-1 gene therapy, is capable to modulate microglia cells and CPu gene expression, leading to an improvement in motor function.Instituto de Investigaciones Bioquímicas de La Plat

Microglia-Specific Expression of Olfml3 Is Directly Regulated by Transforming Growth Factor β1-Induced Smad2 Signaling

Microglia maturation takes place during the postnatal weeks and is characterized by the establishment of a unique microglia-specific gene expression pattern. Tmem119, Fcrls, Hexb, and Olfml3 have been identified among these microglia-specific genes. Transforming growth factor β1 (TGFβ1) has been reported as a critical factor for microglia maturation and maintenance and active TGFβ signaling precedes the inductions of microglial gene expression. In this study, we demonstrate Olfml3 expression in adult microglia and further provide evidence that TGFβ1 induces upregulation of Olfml3 expression in postnatal microglia. Using chromatin immunoprecipitation and microglia-specific silencing of TGFβ signaling in vitro and in vivo, we in clearly show that Olfml3 is a direct TGFβ1/Smad2 target gene. Together, our data underline the importance of TGFβ1 as a critical regulator of microglia functions and microglia maturation and further broaden our understanding of TGFβ1-mediated effects on the resident immune cells of the central nervous system

CD74: a prospective marker for reactive microglia?

Potru P, Spittau B. CD74: a prospective marker for reactive microglia? Neural Regeneration Research . 2023;18(12):2673-2674

Microglial Transforming Growth Factor-β Signaling in Alzheimer’s Disease

Vidovic N, Spittau B. Microglial Transforming Growth Factor-β Signaling in Alzheimer’s Disease. International Journal of Molecular Sciences. 2024;25(6): 3090.Novel technologies such as single-cell RNA and single-nucleus RNA sequencing have shed new light on the complexity of different microglia populations in physiological and pathological states. The transcriptomic profiling of these populations has led to the subclassification of specific disease-associated microglia and microglia clusters in neurodegenerative diseases. A common profile includes the downregulation of homeostasis and the upregulation of inflammatory markers. Furthermore, there is concordance in few clusters between murine and human samples. Apolipoprotein E, which has long been considered a high-risk factor for late-onset Alzheimer’s disease, is strongly regulated in both these murine and human clusters. Transforming growth factor-β plays an essential role during the development and maturation of microglia. In a pathological state, it attenuates their activation and is involved in numerous cell regulatory processes. Transforming growth factor-β also has an influence on the deposition of amyloid-beta, as it is involved in the regulation of key proteins and molecules. Taken together, this review highlights the complex interaction of apolipoprotein E, the triggering receptor on myeloid cells 2, and transforming growth factor-β as part of a regulatory axis in microglia at the onset and over the course of Alzheimer’s disease