Mitochondrial cGAS Inhibitor
Infections by DNA viruses trigger the cytosolic DNA sensor cyclic GMP–AMP synthase (cGAS) and lead to type I IFN expression. Infection can also cause mitochondrial stress and induce the release of mitochondrial DNA, which also can activate cGAS. In this Top Read, Song et al. (p. 2155) characterized proteins in murine macrophages that interact with cGAS during HSV-1 infection. Complement C1q binding protein (C1QBP) was identified as a cGAS interactor and was observed to leak from mitochondria to the cytoplasm during HSV-1 infection. Cytoplasmic C1QBP could bind to the nucleotidyltransferase domain of cGAS and inhibit its enzymatic activity in vitro. C1QBP overexpression in the cytoplasm also inhibited cGAS-driven innate immune responses and made cells more susceptible to HSV-1 infection. In contrast, C1QBP deficiency was associated with enhanced innate immunity and reduced HSV-1 infection. These findings indicate that C1QBP is an inhibitor of cGAS activity that can be released from mitochondria during DNA virus infection.
Term Labor Uterine Inflammation
Maternal peripheral leukocytes infiltrate uterine tissues before, during, and following term labor, and are likely to secrete inflammatory molecules that contribute to inducing labor. In this Top Read, Shynlova et al. (p. 2015) characterized cytokines secreted into conditioned media by primary decidual and myometrial cells from term labor (TL) and term not in labor (TNL) women. Decidual cells from TL secreted proinflammatory cytokines, chemokines, and growth factors, whereas myometrium from TNL secreted chemokines associated with leukocyte infiltration. Treatment of TL decidua with a broad-spectrum chemokine inhibitor was sufficient to inhibit secretion of factors that activate leukocytes. These results highlight contributions made by decidual and myometrial cells in driving labor progression.
Microglial Inflammasome Activation
Neurodegenerative conditions, like Parkinson’s disease, are defined by formation of intraneuronal cytoplasmic inclusions comprised of α-synuclein (α-syn) aggregates. In this Top Read, Scheiblich et al. (p. 2143) characterized different forms of α-syn in activated microglia, immune cells that reside in the CNS. Primary microglia were able to engulf but not degrade α-syn. Moreover, α-syn monomers and oligomers activated NLRP3 inflammasomes via TLR2 and TLR5 in microglia, and NLRP3 activation induced IL-1β secretion, which resulted in a reduced capacity to clear α-syn oligomers. In contrast, α-syn oligomer clearance was improved upon treatment of microglia with a selective NRLP3 inhibitor or in NLRP3-deficient microglia. These results provide insight into the mechanism by which α-syn mediates NLRP3 inflammasome activation in microglia.
In humans, disseminated Cryptococcus neoformans infection has a high mortality rate. In this Top Read, Goughenour et al. (p. 2096) describe the contribution of inducible NO synthase (iNOS) to clearing this environmental fungus from the kidneys of i.v. infected mice. Compared to WT mice, those deficient in iNOS present with increased fungal burden, tissue damage, and myeloid cell recruitment to the kidneys, but not other organs. While iNOS deficiency did not affect the polarization of T cells within the kidney, a paucity of activated T cells was observed. However, iNOS did not play a role in macrophage function, as iNOS deficient macrophages did not display altered activation profiles or deficient antifungal responses. Together, these data suggest iNOS as a critical component to the localized, intrarenal, antifungal response during disseminated C. neoformans infection.