Compared with laboratory environments, complex natural environments promote brain cell proliferation and neurogenesis. Predators are one important feature of many natural environments, but, in the laboratory, predatory stimuli tend to inhibit brain cell proliferation. Often, laboratory predatory stimuli also elevate plasma glucocorticoids, which can then reduce brain cell proliferation. However, it is unknown how natural predators affect cell proliferation or whether glucocorticoids mediate the neurogenic response to natural predators. We examined brain cell proliferation in six populations of the electric fish, Brachyhypopomus occidentalis, exposed to three forms of predator stimuli: (i) natural variation in the density of predatory catfish; (ii) tail injury, presumably from predation attempts; and (iii) the acute stress of capture. Populations with higher predation pressure had lower density of proliferating (PCNAþ) cells, and fish with injured tails had lower proliferating cell density than those with intact tails. However, plasma cortisol did not vary at the population level according to predation pressure or at the individual level according to tail injury. Capture stress significantly increased cortisol, but only marginally decreased cell proliferation. Thus, it appears that the presence of natural predators inhibits brain cell proliferation, but not via mechanisms that depend on changes in basal cortisol levels. This study is the first demonstration of predator-induced alteration of brain cell proliferation in a free-living vertebrate.

The brain structure of many animals is influenced by their predators, but the cellular processes underlying this brain plasticity are not well understood. Previous studies showed that electric fish () naturally exposed to high predator () density and tail injury had reduced brain cell proliferation compared with individuals facing few predators and those with intact tails. However, these field studies described only correlations between predator exposure and cell proliferation. Here, we used a congener and another electric fish to experimentally test the hypothesis that exposure to a predator stimulus and tail injury causes alterations in brain cell proliferation. To simulate predator exposure, we either amputated the tail followed by short-term (1 day) or long-term (17-18 days) recovery or repeatedly chased intact fish with a plastic rod over a 7 day period. We measured cell proliferation (PCNA+ cell density) in the telencephalon and diencephalon, and plasma cortisol, which commonly mediates stress-induced changes in brain cell proliferation. In both species, either tail amputation or simulated predator chase decreased cell proliferation in the telencephalon in a manner resembling the effect of predators in the field. In , cell proliferation decreased drastically in the short term after tail amputation and partially rebounded after long-term recovery. In, tail amputation elevated cortisol levels, but repeated chasing had no effect. In , tail amputation elevated cortisol levels in the short term but not in the long term. Thus, predator stimuli can cause reductions in brain cell proliferation, but the role of cortisol is not clear.

Sterile stimuli can trigger inflammatory responses, and in some cases can lead to a variety of acute or chronic diseases. In this study, we hypothesize that a benzimidazole inhibitor may be used as a therapeutic in the treatment of sterile inflammation. In vitro, this inhibitor blocks TLR signalling and inflammatory responses. The benzimidazole inhibitor does not prevent mouse macrophage activation after stimulation with 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane), a hydrocarbon oil that mimics features of sterile inflammation when injected in vivo. However, C57BL/6J female mice treated with the benzimidazole inhibitor exhibited a significant reduction of pristane-dependent induction of splenocyte number and weight. Conversely, no significant difference was observed in males. Using mass spectrometry, we found that the urine of pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by the benzimidazole inhibitor. To study the mechanism, we showed that pristane-injected mice had increased cell free DNA in serum, which was not impacted by inhibitor treatment. However, chemokine release (e.g. MCP-1, RANTES and TARC) was significantly reduced in inhibitor-treated mice. Thus, the benzimidazole inhibitor might be used as a new drug to block the recruitment of immune cells during sterile inflammatory diseases in humans. Sterile inflammation is defined as an inflammatory condition triggered by sterile stimuli, such as toxins, minerals and chemicals 1,2 , rather than proinflammatory molecules belonging to pathogenic microbes 3. Similar to pathogen-associated inflammation, sterile inflammation can be initiated by activation of Pattern Recognition Receptors (PRRs), including Toll-like Receptors (TLRs), and leads to production of proinflammatory mediators 1. Furthermore, failure to promptly remove or contain agents causing sterile inflammation can be harmful to the host, leading to chronic inflammation. Nevertheless, it is also possible that sterile inflammation opens space for infection or for the microbiome to exacerbate inflammatory events. Examples of sterile inflammatory disorders are ischemia-reperfusion injury 4 , arteriosclerosis 5 , Alzheimer's disease 6 , and other autoinflammatory and autoimmune diseases 7. Although in the last few years several compounds, such as oridonin 8 and CY-09 9 have been shown to elicit potent therapeutic effects in mouse models of inflammatory diseases; the discovery of new possible anti-inflammatory drugs may lead to the development of more effective therapies towards sterile inflammatory diseases. Here, we used a model of sterile inflammation where the triggering agent is 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane). Pristane is a naturally occurring hydrocarbon oil found in small quantities in many plants, in various marine organisms, and as the most active component of mineral oil 10. Importantly, there is evidence that properties of certain hydrocarbons such as pristane can med...

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Interleukin-1 receptor-associated kinase (IRAK) 4 is a serine/threonine kinase involved in TLR/IL-1R responses. Upon TLR/IL-1R activation, autophosphorylation of IRAK4 induces proinflammatory gene transcription. In this study we hypothesize that the kinase activity of IRAK4 may be a druggable target in the treatment of sterile autoinflammation and Lupus. C57BL/6 female mice injected with the hydrocarbon oil Pristane, exhibited a significant Pristane-dependent induction of splenomegaly; whereas treatment with the IRAK4 kinase inhibitor reduced this inflammatory symptom. Conversely, no significant difference was observed in males. Using mass spectrometry, we found that the urine of Pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by IRAK4 kinase inhibition. We showed that Pristane-injected mice had increased cell free DNA in serum, which was not impacted by kinase inhibitor treatment. However, chemokine release was significantly reduced in IRAK4 kinase inhibitor-treated mice. We further analyzed the kinase activity of IRAK4 in MRL-lpr mice, which were compared with MRL-lpr/IRAK4 kinase-inactive (KDKI) mice (where IRAK4 is expressed but its kinase activity is lost). Although MRL-lpr/IRAK4KDKI and MRL-lpr mice did not show differences in CD4+ and CD8+ cells activation, we found a significantly reduced splenomegaly in MRL-lpr/IRAK4KDKI mice compared to controls, also exhibiting a gender bias. Thus, IRAK4 kinase activity might represent a new therapeutic and druggable target in the recruitment of immune cells during sterile inflammatory diseases in humans, including Systemic Lupus Erythematous (SLE).