bioRxiv Science⌕ Search

bioRxiv · 10.1101/2023.06.12.544445

The orientation of choroidal macrophage polarization significantly influences the development of myopia in murine models

Abstract

Myopia is a primary contributor to visual impairment and has emerged as a global public health concern. Evidence indicates that one of the main structural features of myopia is the corresponding decrease in choroidal thickness, and choroidal macrophages play an important role in maintaining the choroidal thickness. Nevertheless, the effect of choroidal macrophages on myopia remains unclear. Here, we discovered that the continuous intraperitoneal injection of clodronate liposomes depleted choroidal macrophages and leads to myopia, which confirmed that the presence of choroidal macrophages plays an important role in myopia development. Subsequently, based on the phenotypic characteristics of macrophages, experiments were designed to study the effects of different polarization directions of macrophages on myopia development. We found that lipopolysaccharides (LPS) injection can induce the polarization of choroidal M1 macrophages, thinning the choroidal thickness and resulting in myopia. Conversely, IL-4 or IL-13 injection causes choroidal M2 macrophage polarization, thickens the choroid, and suppresses the progression of myopia. Additionally, we demonstrated that the opposite effects of M1 and M2 macrophages on myopia development may be related to their impacts on choroidal thickness, inflammation, and oxidative stress response. These findings establish that choroidal macrophages are critically important in the development of myopia and provide new strategies for the development of myopic therapies.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Hou, J., Ikeda, S.-i., Mori, K., Jeong, H., Torii, H., Negishi, K., Tsubota, K., Kurihara, T.. 2023-06-13. The orientation of choroidal macrophage polarization significantly influences the development of myopia in murine models. https://doi.org/10.1101/2023.06.12.544445

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Differential and Cooperative Immunomodulation by Saponin Adjuvants QS-21 and QS-7 in Human THP-1 Macrophages

QS-21, a triterpene glycoside saponin derived from Quillaja saponaria, is a potent immunostimulatory adjuvant incorporated in several FDA-approved vaccines. QS-7, a structurally related saponin fraction, has been reported to retain immunomodulatory activity with reduced hemolytic toxicity; however, its lower natural abundance has limited its systematic immunological characterization. To address this gap, we systematically compare responses to QS-21 and QS-7 in the THP-1 human macrophage model to resolve their distinct and cooperative contributions to antigen presenting cell (APC) activation. Following cytotoxicity profiling to establish safe and biologically relevant dosing, flow cytometry, proteomics, and transcriptomics were used to delineate the immunological programs engaged by each saponin alone and in combination. QS-7 alone induced minimal upregulation of cell surface activation markers and did not elicit a significant transcriptional signature, yet it drove dose-dependent secretion of a broad panel of pro-inflammatory cytokines and chemokines, revealing a dissociation between these two arms of macrophage activation. Strikingly, co-administration of QS-7 with QS-21 substantially potentiated macrophage activation across all parameters tested, amplifying surface marker upregulation, broadening cytokine and chemokine output to include IL-12p70 and IFN-{gamma}, and markedly expanding the pro-inflammatory transcriptional and pathway landscape induced by QS-21, while concurrently suppressing counter-regulatory lipid-sensing pathways (PPAR, RAR, FXR/RXR) that constrain inflammatory output. Collectively, these findings establish QS-7 not merely as an attenuated analog of QS-21, but as a functionally distinct immunomodulator that recalibrates both the magnitude and regulatory tone of QS-21-driven macrophage activation. These findings show that structurally distinct saponins elicit distinct and complementary macrophage responses, providing a foundation for structure-function studies. Together with synthetic biology and data-driven design, this knowledge can guide the development of new-to-nature saponin adjuvants.

immunology↗

MAFB and MAF cooperatively orchestrate human anti-inflammatory macrophage identity via autocrine Interleukin-10

Macrophage lineage identity is governed by intricate transcriptional networks. Although the large MAF basic region-leucine zipper (bZIP) transcription factors MAFB and MAF are critical regulators of anti-inflammatory programs, their molecular coordination and non-redundant contributions within human macrophages remain poorly defined. Here, utilizing integrated proteomic, transcriptomic, and epigenomic profiling, we demonstrate that endogenous MAFB and MAF physically associate to form a stable heterodimeric complex on chromatin in human M-CSF-dependent monocyte-derived macrophages (M-Mac). Genome-wide CUT&Tag mapping reveals a hierarchical epigenomic architecture in which MAFB acts as the primary global anchor of M-Mac identity, whereas MAF provides localized transcriptional tuning. Mechanistically, both factors directly bind the IL10 locus, but functional IL-10 expression is primarily driven by MAFB. Neutralizing antibody assays reveal that endogenously produced IL-10 establishes an obligate autocrine feedback loop mandatory for both the initial acquisition and the maintenance of the M-Mac anti-inflammatory profile. Functionally, MAFB and MAF exert non-redundant control over core macrophage effectors: MAFB dictates apoptotic cell efferocytosis amd T cell activation, whereas MAF modulates phagocytosis, and acts as a brake suppressing acute pro-inflammatory cytokine/chemokine hyper-induction. Together, these findings establish a comprehensive molecular blueprint of how MAFB and MAF cooperatively fine-tune human monocyte-derived macrophage identity and functional plasticity.

immunology↗

Peripheral Immune Cell Shifts Associated With Alzheimer's Disease Vary in Multi-Ancestry Cohorts

Background: Alzheimer's disease (AD) is heavily influenced by immune system dysregulation, yet the role of peripheral immune processes--and how these vary across ethnicities--remains understudied. Objective: To investigate ancestry-specific immune alterations in AD by profiling peripheral immune cell proportions using high-resolution deconvolution of whole blood RNA-sequencing data, characterizing disease associated cell types, and identifying enriched biological pathways. Methods: We analyzed whole blood RNA-seq data from non-Hispanic White (NHW), African American (AA), Caribbean Hispanic (CariHISP), and Peruvian (PERU) individuals, balanced between AD cases and cognitively normal controls. Immune cell proportions were estimated using CIBERSORTx and compared using linear models (propeller R package) adjusted for age, sex, and APOE genotypes in case-control models. Cell-type-specific differential expression was performed using CARseq, and pathway enrichment analyses performed using MSigDB gene sets. Results: Baseline immune composition differed substantially across cohorts for multiple innate and adaptive cell types. In a multi-ethnic AD versus control analysis, eight cell types reached FDR significance: AD was associated with decreased proportions naive B cells, CD56dim NK cells, B cells, intermediate monocyte I, and double-negative T cells, alongside significant expansion in neutrophils and non-classical monocytes. Interaction analyses revealed heterogeneous group-specific effects, with the broadest shifts in AA and CariHISP. Pathway enrichment indicated shared heme metabolism, interferon, and oxidative phosphorylation programs across groups, with distinct emphases: broad, strong heme metabolism enrichment and the highest oxidative phosphorylation signal (in myeloid populations) in AA; MYC targets in naive B cells and eosinophils in CariHISP; dendritic cell - and T follicular helper cell - centered interferon, inflammatory, and proliferative programs in NHW; and TGF-{beta} and apoptosis signatures, unique to PERU, alongside the broadest cell-type coverage. Conclusions: Peripheral immune dysregulation in AD is characterized by depletion of lymphoid and intermediate monocyte populations with concurrent neutrophil and non-classical monocyte expansion, and these patterns vary meaningfully by ancestry. These findings underscore the need for population-informed biomarkers and therapeutic strategies in AD.

immunology↗