Biology subjects

Pearson, G.

Publications and source records attributed to Pearson, G..

5 recordsLinked to original sources

bioRxiv2026

SARM1 is required for macrophage immunophenotype switching that is essential for nerve repair

SARM1 is a key executor of Wallerian degeneration in axons. Global knockout of sarm1 in mice delays degeneration for several weeks. Recently, we reported that Schwann cell reprogramming, inflammation, and axon regeneration are also delayed in these animals. Several studies have also indicated that SARM1 has essential regulatory functions in macrophages (M{phi}). However, the role of SARM1 in M{phi} in the context of peripheral nerve injury remains unknown. Here, we report that loss of sarm1 impairs splenic M{phi} from adopting immunological stimuli driven immunophenotypes in culture. Through a combination of cell culture, Western blotting, gene expression analysis, in vivo injection of M{phi} into sciatic nerves, and generation of cell specific sarm1 conditional knockout mouse lines, we found that SARM1 is required for proper immunophenotypes in M{phi}. Loss of sarm1 in macrophages increases neurite length of sensory neurons in culture but delays regeneration in a model of peripheral nerve injury. We identified dysregulation of several inflammatory and anti-inflammatory immunological stimuli pathways and altered regulation of both iNOS and Arginase-1 in Sarm1-/- M{phi}. In culture, Sarm1-/- M{phi} display difficulty phagocytosing and clearing myelin debris and this was recapitulated in vivo with a M{phi} specific sarm1 knockout line. Generation of M{phi} and neuronal sarm1 conditional knockout mice further indicated that SARM1 is required in both cell types for an efficient response to peripheral nerve injury. This study provides the first evidence that SARM1 signaling in M{phi} is required for injury induced inflammation, degeneration, and axon regeneration.

neuroscience↗

bioRxiv2025

Homeostatic neuroimmune rhythms are linked to priming of olfactory bulb responses to an intranasal inflammatory challenge

The circadian and immune systems are important for tissue homeostasis, yet their integration in the brain remains understudied. The olfactory bulb, a brain region that exhibits robust circadian rhythms and is regularly exposed to inflammatory stimuli, provides an optimal locus to probe the interaction of these two systems. We found that the murine olfactory bulb rhythmically expresses immune-related transcripts, with antiviral transcripts peaking around dusk. This was accompanied by distinct transcriptional responses to intranasal poly(I:C) at dusk versus dawn, suggesting that time of day primes the olfactory bulbs response to inflammatory challenges. Using imaging flow cytometry, we detected two distinct populations of microglia, the resident macrophages of the brain, which differentially responded to intranasal poly(I:C) depending on time of day. This unveils a clear relationship between time of day and olfactory bulb immune processes, suggesting time is an important dimension to consider when studying the olfactory pathway into the brain.

immunology↗

bioRxiv2021

Fibroblast activation protein regulates natural killer cell migration, extravasation and tumor infiltration

Natural killer (NK) cells play a critical role in physiologic and pathologic conditions such as pregnancy, infection, autoimmune disease and cancer. In cancer, numerous strategies have been designed to exploit the cytolytic properties of NK cells, with variable success. A major hurdle to NK-cell focused therapies is NK cell recruitment and infiltration into tumors. While the chemotaxis pathways regulating NK recruitment to different tissues are well delineated, the mechanisms human NK cells employ to physically migrate are ill-defined. We show for the first time that human NK cells express fibroblast activation protein (FAP), a cell surface protease previously thought to be primarily expressed by activated fibroblasts. FAP degrades the extracellular matrix to facilitate cell migration and tissue remodeling. We used novel in vivo zebrafish and in vitro 3D culture models to demonstrate that FAP knock out and pharmacologic inhibition restrict NK cell migration, extravasation, and invasion through tissue matrix. Notably, forced overexpression of FAP promotes NK cell invasion through matrix in both transwell and tumor spheroid assays, ultimately increasing tumor cell lysis. Additionally, FAP overexpression enhances NK cells invasion into a human tumor in immunodeficient mice. These findings demonstrate the necessity of FAP in NK cell migration and present a new approach to modulate NK cell trafficking and enhance cell-based therapy in solid tumors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/429622v3_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@d6d9e5org.highwire.dtl.DTLVardef@17b6790org.highwire.dtl.DTLVardef@cc581eorg.highwire.dtl.DTLVardef@1ad2129_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Immunological and pathological outcomes of SARS-CoV-2 challenge after formalin-inactivated vaccine immunisation of ferrets and rhesus macaques

There is an urgent requirement for safe and effective vaccines to prevent novel coronavirus disease (COVID-19) caused by SARS-CoV-2. A concern for the development of new viral vaccines is the potential to induce vaccine-enhanced disease (VED). This was reported in several preclinical studies with both SARS-CoV-1 and MERS vaccines but has not been reported with SARS-CoV-2 vaccines. We have used ferret and rhesus macaques challenged with SARS-CoV-2 to assess the potential for VED in animals vaccinated with formaldehyde-inactivated SARS-CoV-2 (FIV) formulated with Alhydrogel, compared to a negative control vaccine in ferrets or unvaccinated macaques. We showed no evidence of enhanced disease in ferrets or rhesus macaques given FIV except for mild transient enhanced disease seen at seven days post infection in ferrets. This increased lung pathology was observed early in the infection (day 7) but was resolved by day 15. We also demonstrate that formaldehyde treatment of SARS-CoV-2 reduces exposure of the spike receptor binding domain providing a mechanistic explanation for suboptimal immunity.

pathology↗

bioRxiv2020

TOLLIP promotes durable alveolar macrophage-mediated immunity during Mycobacterium tuberculosis infection by resolving cellular stress from lipids.

Relative deficiency of TOLLIP expression in monocytes is associated with increased tuberculosis (TB) susceptibility in genetic studies, despite antagonizing host innate immune pathways that control Mycobacterium tuberculosis (Mtb) infection. In this study, we investigated the mechanisms by which TOLLIP influences Mtb immunity. Tollip-/- mice developed worsened disease, consistent with prior genetic observations, and developed large numbers of foam cells. Selective TOLLIP deletion in alveolar macrophages (AM) was sufficient to induce lipid accumulation and increased Mtb persistence 28 days after infection, despite increased antimicrobial responses. We analyzed sorted, Mtb-infected Tollip-/- AM from mixed bone marrow chimeric mice to measure global gene expression 28 days post-infection. We found transcriptional profiles consistent with increased EIF2 signaling. Selective lipid administration to Tollip-/- macrophages induced lipid accumulation, and Mtb infection of lipid laden, Tollip-/- macrophages induced cellular stress and impaired Mtb control. EIF2 activation induced increased Mtb replication within macrophages, irrespective of TOLLIP expression, and EIF2 kinases were enriched in human caseous granulomas. Our findings define a critical checkpoint for TOLLIP to prevent lipid-induced EIF2 activation and demonstrate an important mechanism for EIF2 signaling to permit Mtb replication within macrophages.

immunology↗