Key Points C1q can form a multimolecular signaling complex with HMGB1, RAGE, and LAIR-1 in lipid rafts. C1q and HMGB1 together promote monocytes to differentiate to an anti-inflammatory phenotype.

A primary mechanism for activation of innate immunity is recognition of damage or pathogen associated molecular patterns by pattern recognition receptors (PRRs). Nucleic acid is a damage associated molecular pattern molecule that when internalized into a monocyte and recognized by intracellular nucleic acid sensing toll like receptors will cause production of type 1 interferon. The process by which DNA or RNA is delivered into the cytosol of monocytes in systemic lupus erythematosus remains incompletely understood, and therapeutic approaches to prevent DNA-mediated monocyte activation are needed. We identified two mechanisms for internalization of DNA by monocytes. IgG-bound DNA was internalized by interacting with Fc gamma receptor IIa, while high-mobility group box-1 protein-bound DNA was internalized by interacting with the receptor for advanced glycation end products. Both pathways contribute to an inflammatory phenotype in monocytes exposed to serum from patients with SLE. Moreover, both of these pathways can be inhibited by a pentapeptide, DWEYS, which is a DNA mimetope. In one instance DWEYS directly competes with DNA for antibody binding and in the other DWEYS binds high-mobility group box-1 and blocks its interaction with RAGE. Our data highlight distinct pathways involved in nucleic acid enters monocytes in SLE, and identify a potential therapeutic to prevent nucleic acid internalization in SLE.

Systemic infection can initiate or exacerbate central nervous system (CNS) pathology, even in the absence of overt invasion of bacteria into the CNS. Recent epidemiological studies have demonstrated that human survivors of sepsis have an increased risk of long-term neurocognitive decline. There is thus a need for improved understanding of the physiological mechanisms whereby acute sepsis affects the CNS. In particular, MyD88-dependent activation of brain microvascular endothelial cells and a resulting loss of blood-brain barrier integrity have been proposed to play an important role in the effects of systemic inflammation on the CNS. Signaling through the vagus nerve has also been considered to be an important component of CNS responses to systemic infection. Here, we demonstrate that blood-brain barrier permeabilization and hippocampal transcriptional responses during polymicrobial sepsis occur even in the absence of MyD88-dependent signaling in cerebrovascular endothelial cells. We further demonstrate that these transcriptional responses can occur without vagus nerve input. These results suggest that redundant signals mediate CNS responses in sepsis. Either endothelial or vagus nerve activation may be individually sufficient to transmit systemic inflammation to the central nervous system. Transcriptional activation in the forebrain in sepsis may be mediated by MyD88-independent endothelial mechanisms or by non-vagal neuronal pathways.

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Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions that is four times more commonly diagnosed in males than females. While susceptibility genes located in the sex chromosomes have been identified in ASD, it is unclear whether they are sufficient to explain the male bias or whether gonadal hormones also play a key role. We evaluated the sex chromosomal and hormonal influences on the male bias in a murine model of ASD, in which mice are exposed in utero to a maternal antibody reactive to contactin-associated protein-like 2 (Caspr2), which was originally cloned from a mother of a child with ASD (termed C6 mice henceforth). In this model, only male mice are affected. We used the four-core-genotypes (FCG) model in which the Sry gene is deleted from the Y chromosome (Y−) and inserted into autosome 3 (TgSry). Thus, by combining the C6 and FCG models, we were able to differentiate the contributions of sex chromosomes and gonadal hormones to the development of fetal brain and adult behavioral phenotypes. We show that the presence of the Y chromosome, or lack of two X chromosomes, irrespective of gonadal sex, increased the susceptibility to C6-induced phenotypes including the abnormal growth of the developing fetal cerebral cortex, as well as a behavioral pattern of decreased open-field exploration in adult mice. Our results indicate that sex chromosomes are the main determinant of the male bias in the maternal C6-induced model of ASD. The less dominant hormonal effect may be due to modulation by sex chromosome genes of factors involved in gonadal hormone pathways in the brain.

C1q, a component of the classical complement pathway, is required for clearance of apoptotic cells. C1q also regulates activation of innate immune cells through engagement of C1q receptors present on the immune cell surface. C1q deficiency is highly associated with the development of systemic lupus erythematosus (SLE). High Mobility Group Box 1 (HMGB1), a pro-inflammatory mediator, is secreted by inflammatory cells and passively released from necrotic cells. HMGB1 interacts with TLR4 and receptor for advanced glycation end products (RAGE), to augment the production of type 1 interferon and proinflammatory cytokines. Here we show that C1q inhibits HMGB1-mediated monocyte activation through cross-linking RAGE and Leukocyte-associated Ig-like receptor-1 (LAIR-1), which is an inhibitory receptor for collagen and C1q. This crosslinking causes LAIR-1 to enter lipid rafts following HMGB1 and C1q stimulation. C1q suppress HMGB-1 mediated induction of type I-interferon and pro-inflammatory cytokines including IL-12 and TNF-α. Moreover, exposure of monocytes to HMGB1 and C1q together leads to upregulation of a number of anti-inflammatory molecules that might function to induce phagocytosis and to maintain monocyte quiescence. Our results suggest that C1q regulates the activation of innate immunity by HMGB1 and maintains immune homeostasis. These data are consistent with the established requirement for C1q in the prevention of autoimmunity.