A Potential New Use for Tocilizumab: Refractory Checkpoint Inhibitor Hepatitis.

Immune checkpoint inhibitors are becoming more commonly used for many forms of malignancy. With this class of medications being more heavily used, there has been an associated rise in medication-induced autoimmune hepatitis. This case involves a 35-year-old woman being treated with nivolumab/ipilimumab for renal cell carcinoma who developed a steroid-refractory autoimmune hepatitis.

The Role of PDE11A4 in Social Isolation-Induced Changes in Intracellular Signaling and Neuroinflammation.

Phosphodiesterase 11A (PDE11A), an enzyme that degrades cyclic nucleotides (cAMP and cGMP), is the only PDE whose mRNA expression in brain is restricted to the hippocampal formation. Previously, we showed that chronic social isolation changes subsequent social behaviors in adult mice by reducing expression of PDE11A4 in the membrane fraction of the ventral hippocampus (VHIPP). Here we seek extend these findings by determining 1) if isolation-induced decreases in PDE11A4 require chronic social isolation or if they occur acutely and are sustained long-term, 2) if isolation-induced decreases occur uniquely in adults (i.e., not adolescents), and 3) how the loss of PDE11 signaling may increase neuroinflammation. Both acute and chronic social isolation decrease PDE11A4 expression in adult but not adolescent mice. This decrease in PDE11A4 is specific to the membrane compartment of the VHIPP, as it occurs neither in the soluble nor nuclear fractions of the VHIPP nor in any compartment of the dorsal HIPP. The effect of social isolation on membrane PDE11A4 is also selective in that PDE2A and PDE10A expression remain unchanged. Isolation-induced decreases in PDE11A4 expression appear to be functional as social isolation elicited changes in PDE11A-relevant signal transduction cascades (i.e., decreased pCamKIIα and pS6-235/236) and behavior (i.e., increased remote long-term memory for social odor recognition). Interestingly, we found that isolation-induced decreases in membrane PDE11A4 correlated with increased expression of interleukin-6 (IL-6) in the soluble fraction, suggesting pro-inflammatory signaling for this cytokine. This effect on IL-6 is consistent with the fact that PDE11A deletion increased microglia activation, although it left astrocytes unchanged. Together, these data suggest that isolation-induced decreases in PDE11A4 may alter subsequent social behavior via increased neuroinflammatory processes in adult mice.

A genetic basis for friendship? Homophily for membrane-associated PDE11A-cAMP-CREB signaling in CA1 of hippocampus dictates mutual social preference in male and female mice.

Although the physical and mental benefits of friendships are clear, the neurobiological mechanisms driving mutual social preferences are not well understood. Studies in humans suggest friends are more genetically similar, particularly for targets within the 3',5'-cyclic adenosine monophosphate (cAMP) cascade. Unfortunately, human studies can not provide conclusive evidence for such a biological driver of friendship given that other genetically related factors tend to co-segregate with friendship (e.g., geographical proximity). As such, here we use mice under controlled conditions to test the hypothesis that homophily in the cAMP-degrading enzyme phosphodiesterase 11A4 (PDE11A4) can dictate mutual social preference. Using C57BL/6J and BALB/cJ mice in two different behavioral assays, we showed that mice with two intact alleles of Pde11a prefer to interact with Pde11 wild-type (WT) mice of the same genetic background over knockout (KO) mice or novel objects; whereas, Pde11 KO mice prefer to interact with Pde11 KO mice over WT mice or novel objects. This mutual social preference was seen in both adult and adolescent mice, and social preference could be eliminated or artificially elicited by strengthening or weakening PDE11A homodimerization, respectively. Stereotactic delivery of an isolated PDE11A GAF-B domain to the mouse hippocampus revealed the membrane-associated pool of PDE11A-cAMP-CREB signaling specifically within the CA1 subfield of hippocampus is most critical for regulating social preference. Our study here not only identifies PDE11A homophily as a key driver of mutual social preference across the lifespan, it offers a paradigm in which other mechanisms can be identified in a controlled fashion.

Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease.

Many studies implicate altered cyclic nucleotide signaling in the pathophysiology of major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ). As such, we explored how phosphodiesterases 2A (PDE2A) and 10A (PDE10A)-enzymes that break down cyclic nucleotides-may be altered in brains of these patients. Using autoradiographic in situ hybridization on postmortem brain tissue from the Stanley Foundation Neuropathology Consortium, we measured expression of PDE2 and PDE10 mRNA in multiple brain regions implicated in psychiatric pathophysiology, including cingulate cortex, orbital frontal cortex (OFC), superior temporal gyrus, hippocampus, parahippocampal cortex, amygdala, and the striatum. We also assessed how PDE2A and PDE10A expression changes in these brain regions across development using the Allen Institute for Brain Science Brainspan database. Compared to controls, patients with SCZ, MDD and BPD all showed reduced PDE2A mRNA in the amygdala. In contrast, PDE2A expression changes in frontal cortical regions were only significant in patients with SCZ, while those in caudal entorhinal cortex, hippocampus, and the striatum were most pronounced in patients with BPD. PDE10A expression was only detected in striatum and did not differ by disease group; however, all groups showed significantly less PDE10A mRNA expression in ventral versus dorsal striatum. Across development, PDE2A mRNA increased in these brain regions; whereas, PDE10A mRNA expression decreased in all regions except striatum. Thus, PDE2A mRNA expression changes in both a disorder- and brain region-specific manner, potentially implicating PDE2A as a novel diagnostic and/or patient-selection biomarker or therapeutic target.