Muhandes, L. | bioRxiv Science

bioRxiv2022

cGAS/STING-DEPENDENT SENSING OF ENDOGENOUS RNA

Defects in nucleic acid metabolizing enzymes lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing a pathogenic type I interferon response and inflammatory diseases. In these pathophysiological conditions, cGAS-driven IFN production is linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutieres syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling and highlights an important role of the pathway in physiological and pathophysiological innate immune priming. SummaryLoss of the dNTPase and DNA repair enzyme SAMHD1 is associated with cancer and causes systemic autoimmunity. We show transformation-promoting spontaneous DNA damage and MDA5-driven but cGAS/STING-dependent chronic type I interferon production in SAMHD1-deficient mice.

immunology↗

bioRxiv2020

Filaggrin deficient mice have a lower threshold for cutaneous allergen sensitization but do not develop spontaneous skin inflammation or atopy

Defects of filaggrin (FLG) compromise epidermal barrier function and represent an important known genetic risk factor for atopic dermatitis (AD), but also for systemic atopy, including allergic sensitization and asthma. The flaky tail mouse model, widely used to address mechanisms of atopy induction by barrier-defective skin, harbors two mutations that affect the skin barrier, the mutation Flgft, resulting in near-complete loss of FLG expression, and the matted mutation inactivating transmembrane protein 79 (Tmem79). Upon separation of the two mutant loci, which are closely linked on chromosome 3, mice defective only for Tmem79 featured pronounced dermatitis and systemic atopy. Upon extensive backcross to BALB/c, also Flgft/ft mice (assumed to be wild type for Tmem79), developed AD-like dermatitis and reproduced the human atopic march, with high IgE levels and spontaneous asthma, suggesting a key role for functional Flg in protection from atopy also in mice. In contrast, BALB/c mice congenic for a targeted Flg knock out mutation did not develop skin inflammation or atopy. To resolve this discrepancy, we generated Flg-deficient mice on a pure BALB/c background by inactivating the Flg gene in BALB/c embryos. These animals feature an ichthyosis phenotype, but do not develop spontaneous dermatitis or systemic atopy. We sequenced the genome of the atopic Flgft BALB/c congenics and discovered that they were unexpectedly homozygous for the atopy-causing Tmem79matted mutation. In summary, we show that Flg-deficiency does not cause atopy in mice. This finding is in line with lack of atopic disease in a fraction of Ichthyosis vulgaris patients carrying two FLG null alleles. However, absence of FLG may promote and modulate dermatitis caused by other genetic barrier defects, as skin inflammation in Tmem79ma/maFlgft/ft BALB/c congenics is qualitatively different compared to Tmem79ma/ma mice.

immunology↗