Biology subjects

Gao, K. M.

Publications and source records attributed to Gao, K. M..

4 recordsLinked to original sources

bioRxiv2025

Endothelial Cell Expression of STINGV154M Gain-of-Function Mutation Delays the Resolution of UVB-induced Skin Injury

Gain-of-function mutations in STimulator of INterferon Genes (STING) cause STING-Associated Vasculopathy with Onset in Infancy (SAVI), a rare autoinflammatory disease characterized by debilitating inflammatory lung disease and hallmark skin manifestations, such as chilblains and progressive, non-healing ulcers. Mice expressing the most common SAVI-associated variant STINGV154M (VM) recapitulate many clinical features of SAVI, including inflammatory lung disease, but do not develop spontaneous skin lesions. In this study, we show that a single low dose of ultraviolet B (UVB) irradiation, which induces only transient skin inflammation in wild-type (WT) mice, causes severe and progressive skin injury in VM mice. Notably, this phenotype persisted in VM mice depleted of hematopoietic cells and reconstituted with WT bone marrow, demonstrating that STINGV154M expression in non-hematopoietic cells is sufficient to drive persistent skin inflammation. Further analysis identified endothelial cells expressing STINGV154M as the primary driver of the cutaneous phenotype. Flow cytometry and bulk RNA sequencing showed that VM mice exhibited reduced early skin infiltration of macrophages and dendritic cells after UVB exposure. These findings establish a critical link between endothelial STING activation, impaired recruitment of skin myeloid cells, and defective resolution of acute inflammation, offering new insights into the pathogenesis of SAVI-associated skin disease.

immunology↗

bioRxiv2024

IFNγ initiates TLR9-dependent autoimmune hepatitis in DNase II deficient mice

Patients with biallelic hypomorphic mutation in DNASE2 develop systemic autoinflammation and early-onset liver fibrosis. Prior studies showed that Dnase2-/- Ifnar-/- double knockout (DKO) mice develop Type I IFN-independent liver inflammation, but immune mechanisms were unclear. We now show that DKO mice recapitulate many features of human autoimmune hepatitis (AIH), including periportal and interstitial inflammation and fibrosis and elevated ALT. Infiltrating cells include CD8+ tissue resident memory T cells, type I innate lymphoid cells, and inflammatory monocyte/macrophage cells that replace the Kupffer cell pool. Importantly, TLR9 expression by bone marrow-derived cells is required for the the development of AIH. TLR9 is highly expressed by inflammatory myeloid cells but not long-lived Kupffer cells. Furthermore, the initial recruitment of TLR9 expressing monocytes and subsequent activation of lymphocytes requires IFN{gamma} signaling. These findings highlight a critical role of feed forward loop between TLR9 expressing monocyte-lineage cells and IFNg producing lymphocytes in autoimmune hepatitis.

immunology↗

bioRxiv2023

Activation of Autoreactive Lymphocytes in the Lung by STING Gain-of-function Mutation Radioresistant Cells

Gain-of-function mutations in the dsDNA sensing adaptor STING lead to a severe autoinflammatory syndrome known as STING-associated vasculopathy with onset in Infancy (SAVI). SAVI patients develop interstitial lung disease (ILD) and commonly produce anti-nuclear antibodies (ANAs), indicative of concomitant autoimmunity. Mice heterozygous for the most common SAVI mutation, V154M (VM), also develop ILD, triggered by nonhematopoietic VM cells, but exhibit severe peripheral lymphopenia, low serum Ig titers and fail to produce autoantibodies. In contrast, we now show that lethally irradiated VM mice reconstituted with WT stem cells (WT[->]VM chimeras) develop ANAs and lung-reactive autoantibodies associated with accumulation of activated lymphocytes and formation of germinal centers in lung tissues. Moreover, when splenocytes from WT[->]VM chimeras were adoptively transferred into unmanipulated Rag1-/- mice, donor T cells accumulated in the lung. Overall, these findings demonstrate that expression of the VM mutation in non-hematopoietic cells can promote the activation of immunocompetent autoreactive lymphocytes. SummaryChimeric mice expressing STING only in non-hematopoietic cells develop systemic and lung directed autoimmunity which recapitulates what is seen in pediatric patients with SAVI disease.

immunology↗

bioRxiv2023

Expression of a STING Gain-of-function Mutation in Endothelial Cells Initiates Lymphocytic Infiltration of the Lungs

Patients afflicted with STING gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in the initiation of ILD. To identify STING-expressing non-hematopoietic cell types relevant to ILD, we generated a conditional knock-in (CKI) model in which expression of the VM allele was directed to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted expression of the mutant allele resulted in the recruitment of immune cells to the lung and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of SAVI patients or patients afflicted with other ILD-related disorders. SummaryPatients with STING gain-of-function (GOF) mutations develop life-threatening lung autoinflammation. In this study, Gao et al. utilize a mouse model of conditional STING GOF to demonstrate a role for endothelial STING GOF in initiating immune cell recruitment into lung tissues of SAVI mice.

immunology↗