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The sphingolipid sphingosine‐1‐phosphate (S1P) fulfills distinct functions in immune cell biology via binding to five G protein‐coupled receptors. The immune cell‐specific sphingosine‐1‐phosphate receptor 4 (S1pr4) was connected to the generation of IL‐17‐producing T cells through regulation of cytokine production in innate immune cells. Therefore, we explored whether S1pr4 affected imiquimod‐induced murine psoriasis via regulation of IL‐17 production. We did not observe altered IL‐17 production, although psoriasis severity was reduced in S1pr4‐deficient mice. Instead, ablation of S1pr4 attenuated the production of CCL2, IL‐6, and CXCL1 and subsequently reduced the number of infiltrating monocytes and granulocytes. A connection between S1pr4, CCL2, and Mϕ infiltration was also observed in Zymosan‐A induced peritonitis. Boyden chamber migration assays functionally linked reduced CCL2 production in murine skin and attenuated monocyte migration when S1pr4 was lacking. Mechanistically, S1pr4 signaling synergized with TLR signaling in resident Mϕs to produce CCL2, likely via the NF‐κB pathway. We propose that S1pr4 activation enhances TLR response of resident Mϕs to increase CCL2 production, which attracts further Mϕs. Thus, S1pr4 may be a target to reduce perpetuating inflammatory responses.
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2−/− mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2−/− mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2−/− mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2−/− mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2−/− were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2−/− phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.