Jack Humphrey and al.

Here, we present the isoform-centric microglia genomic atlas (isoMiGA), which leverages long-read RNA sequencing to identify 35,879 novel microglia isoforms. We show that these isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ancestry meta-analysis of 555 human microglia short-read RNA sequencing samples from 391 donors, and found associations with genetic risk loci in Alzheimer’s and Parkinson’s disease. We nominate several loci that may act through complex changes in isoform and splice-site usage.

Samantha M. Golomb and al.

As the gut microbiome impacts CNS and peripheral immune activity, we investigated its role in regulating immune response dynamics throughout brain metastasis (BrMet) stages. Antibiotic-induced (ABX) gut dysbiosis significantly increased BrMet burden versus controls but was equalized with fecal matter transplantation, highlighting microbiome diversity as a regulator of BrMet. Single-cell sequencing revealed a highly dynamic immune landscape during BrMet progression in both conditions. However, the timing of the monocyte inflammatory response was altered. Microglia displayed an elevated activation signature in late-stage metastasis in ABX-treated mice. T cell and microglia perturbation revealed involvement of these cell types in modulating BrMet under gut dysbiosis. 

Shunyi Zhao and al.

Microglial GPCRs coupled to a Gi protein  (Gi-GPCRs) play a critical role in microglia-neuron communications. However, the impact of temporally activating microglial Gi signaling on microglial dynamics and neuronal activity in the homeostatic brain remains largely unknown. In this study, we used Gi-based designer receptors exclusively activated by designer drugs (Gi-DREADD) to selectively and temporally modulate microglial Gi signaling pathway. By integrating this chemogenetic approach with in vivo two-photon imaging, we observed that exogenous activation of microglial Gi signaling transiently inhibited microglial process dynamics, reduced neuronal activity, and impaired neuronal synchronization. These altered neuronal functions were associated with a decrease in interactions between microglia and neuron somata. 

Saef Izzy and al.

In the present study, we found that nasal administration of an anti-CD3 monoclonal antibody ameliorated CNS damage and behavioral deficits in a mouse model of contusional traumatic brain injury (TBI). Nasal anti-CD3 induced a population of interleukin (IL)-10-producing regulatory T cells (T_reg cells) that migrated to the brain and closely contacted microglia. T_reg cells directly reduced chronic microglia inflammation and regulated their phagocytic function in an IL-10-dependent manner. Blocking the IL-10 receptor globally or specifically on microglia in vivo abrogated the beneficial effects of nasal anti-CD3. However, the adoptive transfer of IL-10-producing T_reg cells to TBI-injured mice restored these beneficial effects by enhancing microglial phagocytic capacity and reducing microglia-induced neuroinflammation.

Jing-Ping Lin and al.

Using magnetic resonance image (MRI)–guided spatiotemporal RNA profiling in marmoset experimental autoimmune encephalitis (EAE), we mapped lesion dynamics and modeled molecular perturbations relevant to MS. Five distinct lesion microenvironments emerged, involving neuroglial responses, tissue destruction and repair, and brain border regulation. Before demyelination, MRI identified a high ratio of proton density–weighted signal to T1 relaxation time, capturing early hypercellularity, and elevated astrocytic and ependymal senescence signals marked perivascular and periventricular areas that later became demyelination hotspots. As lesions expanded, concentric glial barriers formed, initially dominated by proliferating and diversifying microglia and oligodendrocyte precursors, later replaced by monocytes and lymphocytes. We highlight SERPINE1+ astrocytes as a signaling hub underlying lesion onset in both marmoset EAE and MS.

Sanjana Kumaraguru and al.

Here, we uncovered a dynamic relationship between cortical pyramidal neurons and microglia that tunes microglial numbers and development through distinct phases of mouse postnatal development. Changes in pyramidal cell activity during development induce differential release of activity-dependent proteins such as Activin A, which, in turn, adjusts microglial numbers accordingly. Decoupling of this relationship not only changes microglial numbers but has a long-term consequence on their role as synaptic organizers, which ultimately affects cortical function. 

Georgina V. Long and al.

Here, we present a case of newly diagnosed IDH-wild-type, MGMT promoter unmethylated glioblastome (GBM), treated with a single dose of triplet immunotherapy (anti-PD1 plus anti-CTLA4 plus anti-LAG3) followed by maximal safe resection 12 days later. The anti-PD1 drug was bound to tumor-infiltrating lymphocytes (TILs) in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line combination of checkpoint inhibitors in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927 ).