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Psoriasis is a chronic inflammatory autoimmune skin condition that affects millions of people worldwide. It is driven by IL-17–producing CD4 and γδ T cells and targeted by current anti–IL-17 or anti–IL-23 mAb therapies. These treatments are expensive, increase the risk of opportunistic infections, and do not specifically target the inflammatory cascade. Other cells, including inflammatory monocytes, have been shown to migrate to psoriatic plaques in both human disease and the imiquimod-induced mouse model and could thus constitute potential alternative therapeutic targets. In the mouse, immune modifying particles (IMPs) specifically target Ly6Chi inflammatory monocytes migrating to the site of inflammation, sequestering them in the spleen. In this project, we determined whether IMPs could mitigate the development of imiquimod -induced psoriasis in mice. IMP treatment significantly reduced imiquimod-induced psoriasis severity, decreasing dermal infiltration of Ly6Chi monocytes as well as early-stage monocyte-derived dermal macrophages. This was associated with reduced levels of hallmark cytokines IL-23 and IL-1β as well as associated IL-17–producing γδ T cells. Our work highlights the crucial importance of inflammatory monocytes in the development of this disease as well as a therapeutic potential for IMP in psoriasis.

Current treatment of severe malaria and associated cerebral malaria (CM) and respiratory distress syndromes are directed primarily at the parasite. Targeting the parasite has only partial efficacy in advanced infection, as neurological damage and respiratory distress are due to accumulation of host blood cells in the brain microvasculature and lung interstitium. Here, computational analysis identifies Ly6Clo monocytes as a major component of the immune infiltrate in both organs in a preclinical mouse model. Specifically targeting Ly6Clo monocyte precursors, identified by adoptive transfer, with immune-modifying particles (IMP) prevents experimental CM (ECM) in 50% of Plasmodium berghei ANKA-infected mice in early treatment protocols. Furthermore, treatment at onset of clinical ECM with 2 doses of a novel combination of IMP and anti-malarial drug artesunate results in 88% survival. This combination confers protection against ECM and mortality in late stage severe experimental malaria and provides a viable advance on current treatment regimens., Niewold, Cohen et al. identify Ly6Clo monocytes as a major component of immune cell sequestration in a mouse model of severe malaria. They show that combined immune-modifying particles and anti-malarial drug treatment at the onset of disease signs results in 88% survival of malaria-infected mice.

Highlights • Virus encephalitis and EAE drive marked myeloid generation and migration into the CNS. • Large numbers of antigen-specific T cells infiltrate the CNS in both diseases. • In viral encephalitis immigrating monocytes differentiate into lethal macrophages. • In EAE immigrating monocytes differentiate into dendritic cells. • This differential regulation in the inflamed CNS is poorly understood., Over the last three decades it has become increasingly clear that monocytes, originally thought to have fixed, stereotypic responses to foreign stimuli, mediate exquisitely balanced protective and pathogenic roles in disease and immunity. This balance is crucial in core functional organs, such as the central nervous system (CNS), where minor changes in neuronal microenvironments and the production of immune factors can result in significant disease with fatal consequences or permanent neurological sequelae. Viral encephalitis and multiple sclerosis are examples of important human diseases in which the pathogenic contribution of monocytes recruited from the bone marrow plays a critical role in the clinical expression of disease, as they differentiate into macrophage or dendritic cells in the CNS to carry out effector functions. While antigen-specific lymphocyte populations are central to the adaptive immune response in both cases, in viral encephalitis a prominent macrophage infiltration may mediate immunopathological damage, seizure induction, and death. However, the autoimmune response to non-replicating, non-infectious, but abundant, self antigen has a different disease progression, associated with differentiation of significant numbers of infiltrating monocytes into dendritic cells in the CNS. Whilst a predominant presence of macrophages or dendritic cells in the inflamed CNS in viral encephalitis or multiple sclerosis is well described, the way in which the inflamed CNS mobilizes monocytes in the bone marrow to migrate to the CNS and the key drivers that lead to these specific differentiation pathways in vivo are not well understood. Here we review the current understanding of factors facilitating inflammatory monocyte generation, migration and entry into the brain, as well as their differentiation towards macrophages or dendritic cells in viral and autoimmune disease in relation to their respective disease outcomes.

Neurotropic flaviviruses are transmitted by arthropod vectors largely in an enzootic cycle that frequently involves humans incidentally. They are perhaps the most widespread of all viruses and continue to pose a threat, with increasing global warming, air travel and the extension of their insect vector habitat due to expanding human activity. Infection by these viruses is associated with a significant immunopathological response in a minority of individuals who, if they survive, may endure permanent neurological sequelae. While universal immunisation remains the ideal to prevent infection, progress has been slow and even available vaccines may not reach target populations. Unfortunately, our understanding of the interaction of these viruses with the mammalian host is still rudimentary, making current treatment approaches to disease at best empirical. However, recently, in addition to inhibition of the immunopathogenic activity of cells in situ, approaches to reducing the massive pathogenic leukocyte immigration into the central nervous system (CNS) have targeted monocytes with significant success in animal models. The universality of this population across a wide spectrum of diseases may enable a finely tuned approach to reducing the pathogenic component in encephalitis without interfering with the generation of immunity.