Biology subjects

jin, l.

Publications and source records attributed to jin, l..

5 recordsLinked to original sources

bioRxiv2026

Natural Selection of the Common STING Allele HAQ in Anatomically Modern Humans

The STING allele R71H-G230A-R293Q (HAQ) was positively selected in Anatomically Modern Humans (AMH) during the Out of Africa (OoA) migration. Here, we show that 51.61% of Native Americans (NAM) are HAQ/HAQ, while only 6.45% are WT/WT. HAQ individuals are defective in DNA-induced type I IFNs responses, such as smallpox-induced IFN-alpha production. 82.3% of NAM carry the HAQ allele, which helps explain the post-Columbus NAM population collapse from the smallpox epidemic. Similarly, in 12 sub-groups of Sub-Saharan Africans, we found 0% HAQ/HAQ, indicating ongoing negative selection reflecting Sub-Saharan Africa as the world's heaviest infectious-disease region. To understand positive selection of HAQ in non-Africans, we dephased HAQ haplotypes in 74 sub-populations worldwide, across more than 4,000 individuals. We found that the HAQ allele evolved faster than the neutral H232 STING allele and had more generations during the OoA migration, increasing its frequency in non-Africans. A mouse model of HAQ housed in a Specific Pathogen-Free mouse facility generates more surviving pups than the H232 mice. In summary, the HAQ allele was positively selected during OoA migration but is negatively selected in Sub-Saharan Africa, underscoring its essential role in AMH adaptation to diverse environments.

genetics↗

bioRxiv2026

GYS2 Promotes the Progression of Aortic Dissection and Aortic Aneurysm via C5a/NF-κB-Mediated Pro-Inflammatory Macrophage Polarization

BackgroundAortic aneurysm and aortic dissection (AAD) are lethal cardiovascular emergencies characterized by sudden onset and extremely high early mortality. The pro-inflammatory polarization of macrophages is one of the core factors driving the pathogenesis of AAD, but its underlying mechanism remains unclear. This study focuses on the aberrant expression of glycogen synthase 2 (GYS2) in the AAD microenvironment and its role in driving macrophage polarization toward the pro-inflammatory M1 phenotype. MethodsProteomic analysis was conducted to identify protein heterogeneity associated with AAD. Clinical and animal samples were used to evaluate the correlation between GYS2 expression and AAD progression. Whole-body GYS2 knockout mice and adeno-associated virus (AAV)-mediated macrophage-specific gain- and loss-of-function models were utilized to investigate the regulatory role of GYS2 in macrophage polarization and complement activation. Downstream molecular pathways were identified and validated through in vitro stimulation and in vivo exogenous C5a rescue experiments. ResultsGYS2 expression was significantly upregulated in AAD tissues and primarily localized in macrophages. Activation of GYS2 by LiCl or macrophage-specific overexpression of GYS2 exacerbated aortic dilation and extracellular matrix degradation, and increased mortality in AAD mice. Conversely, whole-body GYS2 knockout or macrophage-specific GYS2 knockdown suppressed inflammatory factors, significantly reduced the incidence of AAD, and attenuated vascular injury. Mechanistically, excessive GYS2 in macrophages specifically triggered the complement-coagulation cascade, promoting the generation of the potent anaphylatoxin C5a. C5a further bound to its receptor C5AR1, activating the downstream PLC{beta}3/NF-{kappa}B signaling pathway, thereby inducing M1 macrophage polarization and matrix metalloproteinase-mediated extracellular matrix degradation. In vivo exogenous C5a rescue completely reversed the vascular protective effects conferred by GYS2 deficiency. ConclusionsThis study demonstrates that highly expressed GYS2 regulates the pro-inflammatory polarization of macrophages and extracellular matrix degradation via the complement C5a/PLC{beta}3/NF-{kappa}B signaling axis, which is a key mechanism driving AAD progression. Specific inhibition of macrophage GYS2 can effectively alleviate aortic vascular inflammation and prevent AAD progression, providing a promising novel strategy for the clinical conservative treatment of AAD.

Molecular Biology↗

bioRxiv2023

The common TMEM173 HAQ, AQ alleles rescue CD4 T cell death, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

The significance of STING (encoded by the TMEM173 gene) in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human TMEM173 alleles R71H-G230A-R293Q (HAQ) and G230A-R293Q (AQ) are carried by [~]60% of East Asians and [~]40% of Africans, respectively. Here, we examine the modulatory effects of HAQ, AQ alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using STING knock-in mice expressing common human TMEM173 alleles HAQ, AQ, and Q293, we found that HAQ, AQ, and Q293 splenocytes resist STING-mediated cell death ex vivo, establishing a critical role of STING residue 293 in cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice did not have CD4 T cellpenia. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more ([~]10-fold, [~]20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they have comparable TBK1, IRF3, and NF{kappa}B activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant HAQ, AQ alleles. STING research and STING-targeting immunotherapy should consider TMEM173 heterogeneity in humans. TeaserCommon human HAQ, AQ TMEM173 alleles dominate the gain-of-function SAVI(N154S) TMEM173 mutant in mice.

immunology↗

bioRxiv2022

Cell dichotomous role of STING in pulmonary hypertension

RationalePatients with constitutive activation of DNA sensing pathway through stimulator of interferon genes (STING), such as those with STING-Associated Vasculopathy with onset in Infancy (SAVI), frequently have complications related to pulmonary hypertension (PH). However, the role of STING-signaling in adult PH patients is heretofore undescribed. ObjectiveTo investigate the role of STING in PH development. Methods and ResultsPH was induced in global STING deficient or cell-specific STING deficient mice using either bleomycin or chronic hypoxia exposure. PH development was evaluated with right ventricular systolic pressure, Fulton index, histological and flow cytometric measurements. STING expression in patient lungs were examined using both immunohistochemistry and flow cytometry. Herein, we describe how STING overactivation in a SAVI mouse model results in a baseline elevation in pulmonary pressures, while global STING deficiency protects mice from PH development. Furthermore, STING-associated PH appears to be independent of type I Interferon (IFN) signaling. We further demonstrate a cellular dichotomous role of STING in PH development with STING expression by smooth muscle cells contributing to PH, and its activation on myeloid cells being pivotal in severe disease prevention. Finally, we demonstrate a STING-PD-L1 axis as necessary for disease progression, suggesting future potential therapeutic applications. ConclusionsOverall, these data provide concrete evidence of STING involvement in PH, establishing biologic plausibility for STING-related therapies in PH treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/518422v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@7f5b50org.highwire.dtl.DTLVardef@143e485org.highwire.dtl.DTLVardef@4fe1a4org.highwire.dtl.DTLVardef@66fe26_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Mucosal vaccine adjuvant cyclic di-GMP differentiates lung moDCs into Bcl6+ and Bcl6- mature moDCs to induce lung memory CD4+ TH cells and lung TFH cells respectively

Induction of lung T-cell responses, including memory CD4+ TH and TFH cells, are highly desirable for vaccines against respiratory infections. We recently showed that the non-migratory monocytes-derived DCs (moDCs) induced lung TFH cells. However, the DCs subset inducing lung CD4+ memory TH cells is unknown. Here, using conditional knockout mice and adoptive cell transfer, we first established that moDCs are essential for lung mucosal, but are dispensable for systemic, vaccine responses. Next, we showed that intranasal administration of adjuvant cyclic di-GMP differentiated lung moDCs into Bcl6+ and Bcl6- moDCs promoting lung memory TH cells and lung TFH cells, respectively. Mechanistically, soluble TNF from lung TNFR2+ cDC2 subpopulation mediates the induction of lung Bcl6+ moDCs. Last, we designed fusion proteins targeting soluble or transmembrane TNF to lung moDCs and generated Bcl6+, Bcl6- lung moDCs respectively. Together, our study revealed lung mature moDCs heterogeneity and showed a moDCs-targeting strategy to enhance lung mucosal vaccine responses.

immunology↗