Biology subjects

Nakahashi-Oda, C.

Publications and source records attributed to Nakahashi-Oda, C..

5 recordsLinked to original sources

bioRxiv2026

CD300a Blockade attenuates renal fibrosis by enhancing macrophage efferocytosis and neutrophil MMP9 production

Renal fibrosis represents an irreversible endpoint of chronic kidney disease. Although macrophage efferocytosis regulates the response to acute renal injury, the mechanisms by which early efferocytosis confers long-term protection against chronic fibrosis remain elusive. Here, we show that phagocyte-specific deletion of the inhibitory receptor CD300a (Cd300afl/flLyz2-Cre) mitigates obstructive renal injury and subsequent fibrosis. CD300a deficiency enhanced efferocytosis by tissue-resident macrophages during the early phase of injury, thereby suppressing the release of damage-associated molecular patterns (DAMPs) and TGF-{beta} expression. This early attenuation of the inflammatory microenvironment altered the composition of recruited neutrophils, shifting them from profibrotic SiglecF+ toward non-profibrotic SiglecF- subsets. Furthermore, loss of CD300a cell-autonomously primed neutrophils for enhanced matrix metalloproteinase-9 (MMP9) production upon injury, whereas neutrophil depletion abolished the protective effect of CD300a deficiency. Importantly, administration of a neutralizing anti-CD300a antibody to wild-type mice recapitulated these protective effects, promoting the shift toward SiglecF- neutrophils and significantly attenuating renal fibrosis. Together, our findings identify CD300a as a regulator of early macrophage efferocytosis and neutrophil-derived MMP9 production, and establish pharmacological CD300a blockade as a potential therapeutic strategy for progressive renal fibrosis.

immunology↗

bioRxiv2026

Soluble CD155 immune complexes reprogram DNAM-1 signaling to potentiate antitumor immunity

Resistance to immune checkpoint inhibitors (ICIs) remains a major challenge in oncology, yet the mechanisms that selectively disable activating pathways are poorly defined. Here, we identify tumor-derived soluble CD155 (sCD155) as a systemic checkpoint that rewires DNAM-1 signaling to drive immunotherapy resistance. High plasma sCD155 levels correlate with impaired anti-PD-1 responses in patients with non-small cell lung cancer. Mechanistically, sCD155 selectively suppresses DNAM-1-dependent activation of CD8+ T and NK cells, uncoupling ICIs from cytotoxic function. Intriguingly, a selective anti-sCD155 monoclonal antibody does not neutralize the ligand, but rather converts it into an activating scaffold. This complex induces Fc{gamma}R-anchored DNAM-1 microcluster formation and robust downstream signaling, effectively switching the checkpoint into a co-stimulatory signal. This reprogramming restores CTL function, suppresses metastasis, and augments PD-1/TIGIT blockade to achieve durable immunity. Our findings establish antibody-mediated receptor architecture rewiring as a therapeutic principle to overcome cancer immune resistance.

immunology↗

bioRxiv2026

DNAM-1 immunoreceptor integrates innate and adaptive immune programs to drive intestinal inflammation

Innate and adaptive immune responses play critical roles in the pathogenesis of inflammatory bowel disease (IBD), yet the molecular pathways integrating these responses remain elusive. Here, we identify DNAM-1 immunoreceptor as a central driver of colitis through distinct, cell type-specific mechanisms. Transcriptomic analyses of human and murine group 3 innate lymphoid cells (ILC3s) revealed DNAM-1 as a conserved IL-23-responsive surface molecule associated with inflammatory cytokine production. In an innate immune-driven anti-CD40 monoclonal antibody (mAb)-induced colitis model, DNAM-1 expressed on ILC3s promoted intestinal inflammation by enhancing IL-22 and GM-CSF production via the integration of the Akt-mTORC1-HIF-1 signaling pathway. Genetic ablation or antibody-mediated blockade of DNAM-1 attenuated inflammatory cytokine production and disease severity. Paradoxically, in T cell-dependent colitis, DNAM-1 expression on dendritic cells, but not on ILC3s or CD4 T cells, exacerbated disease by promoting dendritic cell activation and pathogenic Th1 and Th17 differentiation. Notably, therapeutic blockade of DNAM-1 ameliorated disease in both colitis models and exerted complementary effects when combined with anti-TNF therapy, accompanied by modulation of immune activation programs distinct from those regulated by TNF inhibition. Collectively, these findings establish DNAM-1 as a pivotal regulator of intestinal inflammation bridging innate and adaptive immunity and identify DNAM-1 blockade as a next-generation therapeutic strategy for IBD. Highlight{blacktriangleright} DNAM-1 is an IL-23-responsive receptor conserved in human and mouse ILC3s. {blacktriangleright}DNAM-1 on ILC3s drives innate colitis via Akt-mTORC1-HIF-1 signaling. {blacktriangleright}DNAM-1 on DCs promotes T cell-dependent colitis by inducing Th1/Th17 cells. {blacktriangleright}DNAM-1 blockade targets immune pathways distinct from TNF inhibition. {blacktriangleright}Combined DNAM-1 and TNF blockade shows additive therapeutic efficacy in colitis.

immunology↗

bioRxiv2020

Tumor-derived extracellular vesicles regulate tumor-infiltrating regulatory T cells via the immunoreceptor CD300a

Although tumor-infiltrating regulatory T (Treg) cells play a pivotal role in tumor immunity, how Treg cell activation are regulated in tumor microenvironments remains unclear. Here, we found that mice deficient in the inhibitory immunoreceptor CD300a on their dendritic cells (DCs) have increased numbers of Treg cells in tumors and greater tumor growth compared with wild-type mice after transplantation of B16 melanoma. Pharmacological impairment of extracellular vesicle (EV) release decreased Treg cell numbers in CD300a-deficient mice. Coculture of DCs with tumor-derived EV (TEV) induced the internalization of CD300a and the incorporation of EVs into endosomes, in which CD300a inhibited TEV-mediated TLR3-TRIF signaling for activation of the IFN-{beta}-Treg cells axis. We also show that higher expression of CD300A was associated with decreased tumor-infiltrating Treg cells and longer survival time in patients with melanoma. Our findings reveal the role of TEV and CD300a on DCs in Treg cell activation in the tumor microenvironment.

cancer biology↗

bioRxiv2018

A long-chain fatty acid elongase Elovl6 regulates mechanical damage-induced keratinocyte death and skin inflammation

Mechanical damage on the skin not only affect the barrier function but also induce various immune responses, which trigger or exacerbate the inflammation in healthy individuals and patients with inflammatory skin diseases. However, how mechanical damage-induced skin inflammation is regulated remains largely unknown. Here, we show that mechanical damage due to tape stripping triggered keratinocyte death and release of danger-associated molecular patterns (DAMPs) such as high-mobility group box 1 protein (HMGB-1) and IL-1, which induced production of proinflammatory cytokines and chemokines IL-1{beta} and CXCL-1 by keratinocytes in mice. We also show that a long-chain fatty acid elongase Elovl6 is expressed in keratinocytes. Mice deficient in Elovl6 had increased epidermal levels of cis-vaccenic acid (CVA); this accelerated keratinocyte death triggered by tape stripping and release of DAMPs and exacerbated skin inflammation. Our results demonstrate that Elovl6 regulates mechanical damage-triggered keratinocyte death and skin inflammation.

immunology↗