Upgrading from iMac to iMicro.

In this issue of Immunity, Takata et al. (2017) describe a novel method to differentiate macrophages from iPSCs. These cells, which they call iMacs, are similar to yolk-sac-derived macrophages and are capable of undergoing terminal differentiation into tissue-resident-like macrophages in vitro and in vivo.

NF-κB inducing kinase (NIK) is an essential post-transcriptional regulator of T-cell activation affecting F-actin dynamics and TCR signaling.

NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T cells using T-cell specific NIK-deficient (NIKΔT) mice. Despite showing normal development of lymphoid organs, NIKΔT mice were resistant to induction of CNS autoimmunity. T cells from NIKΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK-/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dynamics. In line with this we found that NIK-deficient T cells were hampered in phosphorylation of Zap70, LAT, AKT, ERK1/2 and PLCγ upon TCR engagement. Hence, our data disclose a hitherto unknown function of NIK in T-cell priming and differentiation.

Imiquimod-Induced Psoriasis in Mice Depends on the IL-17 Signaling of Keratinocytes.

The pathology of psoriasis strongly depends on IL-17A. Monoclonal antibodies blocking either the cytokine or its receptor are among the most efficient treatments for psoriatic patients. Keratinocytes can be activated upon exposure to IL-17A and tumor necrosis factor-α and secrete secondary cytokines and chemokines in the inflamed skin. In psoriasis and its imiquimod-induced mouse model, a strong skin infiltration of neutrophils and inflammatory monocytes can be observed. However, to date, it is not clear how exactly those cellular populations are attracted to the skin and how they contribute to the pathogenesis of the disease. To define the crucial cell type responding to IL-17 and initiating the downstream pathology in psoriasis-like dermatitis, we used mice specifically lacking the IL-17 receptor (IL-17RA) in different cell types. Deletion of IL-17RA in T cells or myeloid had no impact on disease development. Only deletion of this receptor in keratinocytes reflected the full-body deletion of IL-17RA, resulting in strongly reduced dermatitis development. Imiquimod treatment of those IL-17 signaling-deficient mice maintained high monocytic infiltration but failed to attract neutrophils into the skin. We conclude that keratinocytes are a critical cellular target for IL-17A-mediated neutrophil attraction and psoriasis development.

The STATe of the Neuron Leads to Synaptic Stripping.

In a recent issue of Cell, Di Liberto et al. (2018) elucidate the mechanisms involved in synaptic stripping during viral infection. Infected neurons orchestrate their own synaptic loss downstream of IFNγ signaling, ultimately attracting phagocytic monocytes into the CNS through CCL2 production.

New insights into the roles of the contactin cell adhesion molecules in neural development.

In vertebrates, the contactin (CNTN) family of neural cell recognition molecules includes six related cell adhesion molecules that play non-overlapping roles in the formation and maintenance of the nervous system. CNTN1 and CNTN2 are the prototypical members of the family and have been involved, through cis- and trans-interactions with distinct cell adhesion molecules, in neural cell migration, axon guidance, and the organization of myelin subdomains. In contrast, the roles of CNTN3-6 are less well characterized although the generation of null mice and the recent identification of a common extracellular binding partner have considerably advanced our grasp of their physiological roles in particular as they relate to the wiring of sensory tissues. In this review, we aim to present a summary of our current understanding of CNTN functions and give an overview of the challenges that lie ahead in understanding the roles these proteins play in nervous system development and maintenance.

Receptor-type tyrosine phosphatase ligands: looking for the needle in the haystack.

Reversible protein phosphorylation plays a pivotal role in intercellular communication. Together with protein tyrosine kinases, protein tyrosine phosphatases (PTPs) are involved in the regulation of key cellular processes by controlling the phosphorylation levels of diverse effectors. Among PTPs, receptor-like protein tyrosine phosphatases (RPTPs) are involved in important developmental processes, particularly in the formation of the nervous system. Until recently, few ligands had been identified for RPTPs, making it difficult to grasp the effects these receptors have on cellular processes, as well as the mechanisms through which their functions are mediated. However, several potential RPTP ligands have now been identified to provide us with unparalleled insights into RPTP function. In this review, we focus on the nature and biological outcomes of these extracellular interactions between RPTPs and their associated ligands.

Varicones and growth cones: two neurite terminals in PC12 cells.

The rat adrenal pheochromocytoma PC12 cell line is one of the traditional models for the study of neurite outgrowth and growth cone behavior. To clarify to what extent PC12 neurite terminals can be compared to neuronal growth cones, we have analyzed their morphology and protein distribution in fixed PC12 cells by immunocytochemistry. Our results show that that PC12 cells display a special kind of neurite terminal that includes a varicosity in close association with a growth cone. This hybrid terminal, or "varicone", is characterized by the expression of specific markers not typically present in neuronal growth cones. For example, we show that calpain-2 is a specific marker of varicones and can be detected even before the neurite develops. Our data also shows that a fraction of PC12 neurites end in regular growth cones, which we have compared to hippocampal neurites as a control. We also report the extraordinary incidence of varicones in the literature referred to as "growth cones". In summary, we provide evidence of two different kinds of neurite terminals in PC12 cells, including a PC12-specific terminal, which implies that care must be taken when using them as a model for neuronal growth cones or neurite outgrowth.