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1. The circadian clock regulates receptor-mediated immune responses to an herbivore-associated molecular pattern

   https://doi.org/10.1101/2024.11.06.622352  

   Guayazán_Palacios, Natalia; Imaizumi, Takato; Steinbrenner, Adam D (November 2024, bioRxiv)

   Summary Plants activate induced defenses through the recognition of molecular patterns. Like pathogen-associated molecular patterns (PAMPs), herbivore-associated molecular patterns (HAMPs) can be recognized by cell surface pattern recognition receptors leading to defensive transcriptional changes in host plants. Herbivore-induced defensive outputs are regulated by the circadian clock, but the underlying molecular mechanisms remain unknown. To investigate how the plant circadian clock regulates transcriptional reprogramming of a specific HAMP-induced pathway, we characterized the daytime and nighttime transcriptional response to caterpillar-derived In11 peptide, in the legume crop cowpea (Vigna unguiculata). Using diurnal and free-running conditions, we found that daytime In11 elicitation resulted in stronger late-induced gene expression than nighttime. Plants with a conditional arrhythmic phenotype in constant light (LL) conditions lost time-of-day dependent responses to In11 treatment, and this was associated with arrhythmic expression of circadian clock core transcription factorLate Elongated Hypocotyl VuLHY1andVuLHY2. Reporter assays with VuLHY homologs indicated that they interact with the promoter of daytime In11-inducedKunitz Trypsin Inhibitor(VuKTI) via a canonical and a polymorphic CCA1/LHY Binding Site (CBS), consistent with a mechanism of direct regulation by circadian clock transcription factors. This study improves our understanding of the time-dependent mechanisms that regulate herbivore-induced gene expression. 

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2. Innate immunity of surfactant protein A in experimental otitis media

   https://doi.org/10.1177/1753425919866006  

   Abdel-Razek, Osama; Ni, Lan; Yang, Fengyong; Wang, Guirong (August 2019, Innate Immunity)

   Surfactant protein A (SP-A) plays an important role in innate immune response and host defense against various microorganisms through opsonization and complement activation. To investigate the role of SP-A in non-typeable Haemophilus influenzae (NTHi)-induced acute otitis media, this study used wild type C57BL/6 (WT) and SP-A knockout (KO) mice. We divided mice into an infection group in which the middle ear (ME) was injected with NTHi and a control group that received the same treatment using normal saline. Mice were sacrificed on d 1, 3, and 7 after treatment. Temporal bone samples were fixed for histological, cellular, and molecular analyses. Ear washing fluid (EWF) was collected for culture and analyses of pro-inflammatory cytokines and inflammatory cells. SP-A-mediated bacterial aggregation and killing and phagocytosis by macrophages were studied in vitro. SP-A expression was detected in the ME and Eustachian tube mucosa of WT mice but not KO mice. After infection, KO mice showed more severe inflammation evidenced by increased ME mucosal thickness and inflammatory cell infiltration and higher NF-κB activation compared to WT mice. The levels of IL-6 and IL-1β in the EWF of infected KO mice were higher compared to infected WT mice on d 1. Our studies demonstrated that SP-A mediated NTHi aggregation and killing and enhanced bacterial phagocytosis by macrophages in vitro and modulated inflammation of the ME in otitis media in vivo. 

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3. NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1

   https://doi.org/10.1371/JOURNAL.PGEN.1009933  

   Shen, Yang; Endale, Mehari; Wang, Wei; Morris, Andrew R.; Francey, Lauren J.; Harold, Rachel L.; Hammers, David W.; Huo, Zhiguang; Partch, Carrie L.; Hogenesch, John B.; et al (November 2021, PLOS Genetics)

   Kramer, Achim (Ed.)

   In mammals, the circadian clock coordinates cell physiological processes including inflammation. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-κB in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-κB subunit RELA in the human U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude, its inhibition lengthened period length and caused amplitude phenotypes. NF-κB perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity behavior under different light/dark conditions. We show that RELA, like the clock repressor CRY1, repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA binds to the transactivation domain of BMAL1. These data support a model in which NF-kB competes with CRY1 and coactivator CBP/p300 for BMAL1 binding to affect circadian transcription. This is further supported by chromatin immunoprecipitation analysis showing that binding of RELA, BMAL1 and CLOCK converges on the E-boxes of clock genes. Taken together, these data support a significant role for NF-κB in directly regulating the circadian clock and highlight mutual regulation between the circadian and inflammatory pathways. 

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4. Time of the day prioritizes the pool of translating mRNAs in response to heat stress

   https://doi.org/10.1093/plcell/koab113  

   Bonnot, Titouan; Nagel, Dawn H. (April 2021, The Plant Cell)

   Abstract The circadian clock helps organisms to anticipate and coordinate gene regulatory responses to changes in environmental stimuli. Under growth limiting temperatures, the time of the day modulates the accumulation of polyadenylated mRNAs. In response to heat stress, plants will conserve energy and selectively translate mRNAs. How the clock and/or the time of the day regulates polyadenylated mRNAs bound by ribosomes in response to heat stress is unknown. In-depth analysis of Arabidopsis thaliana translating mRNAs found that the time of the day gates the response of approximately one-third of the circadian-regulated heat-responsive translatome. Specifically, the time of the day and heat stress interact to prioritize the pool of mRNAs in cue to be translated. For a subset of mRNAs, we observed a stronger gated response during the day, and preferentially before the peak of expression. We propose previously overlooked transcription factors (TFs) as regulatory nodes and show that the clock plays a role in the temperature response for select TFs. When the stress was removed, the redefined priorities for translation recovered within 1 h, though slower recovery was observed for abiotic stress regulators. Through hierarchical network connections between clock genes and prioritized TFs, our work provides a framework to target key nodes underlying heat stress tolerance throughout the day. 

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5. Oxytocin impairs wound-healing during social isolation but not social living

   https://doi.org/10.1016/j.psyneuen.2025.107445  

   Hammond, Emma; Monari, Patrick; Kilponen, Lila; Chen, Yiru; Auger, Anthony; Marler, Catherine (June 2025, Psychoneuroendocrinology)

   Social isolation hampers immune system function, and the biological mechanisms driving this effect remain understudied. We hypothesized that oxytocin (OT), a key neuropeptide involved in social cognition, is a critical mediator of social context on immune function. In the California mouse (Peromyscus californicus), we examined how female and male immune function is influenced by (1) social isolation from same-sex peers, (2) social peer affiliation, and (3) exogenous OT. We evaluated immune function through wound size progression following a skin biopsy and proinflammatory cytokines in the wound fluid. Unexpectedly, social isolation alone did not influence wound healing, but isolation +OT increased wound size in a dose dependent manner. Wound size progression interacted with sex and OT in socially-housed mice, suggesting that OT increases inflammation in females, while decreasing inflammation in males in a social context-dependent manner. Inflammatory biomarker interleukin-6 (IL-6) mRNA expression correlated with wound size overall, supporting wound healing as an index of inflammatory response. However, isolation +OT mice did not have higher levels of IL-6, suggesting that the mechanism through which isolation +OT influences wound size is not through IL-6 activity. Behaviorally, higher levels of affiliation were negatively associated with wound size, and this effect was diminished by OT treatment. Our results highlight that the anti-inflammatory effects of OT are likely highly dependent on social context. 

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