Krabbe G, Minami SS, Etchegaray JI, Taneja P, Djukic B, Davalos D, Le D, Lo I, Zhan L, Reichert MC, Sayed F, Merlini M, Ward ME, Perry DC, Lee SE, Sias A, Parkhurst CN, Gan WB, Akassoglou K, Miller BL, Farese RV Jr, Gan L. Microglial NFκB-TNFα hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia. Proc Natl Acad Sci U S A. 2017 May 9;114(19):5029-5034. Epub 2017 Apr 24 PubMed.

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  1. This is a fascinating report using fly models to examine the intersection of aging, neurodegeneration, and metabolism. While flies don’t have a true microglial analog, they do have a multifunctional type of glial cell. Studies from Marc Freeman’s lab demonstrate “phagocytic” or “ensheathing” glia that take on some of the functionality of microglia in mammals. In this paper, ablation of NF-κB signaling impacts the cerebral innate immune/inflammatory response. When the authors dampen NF-κB, there is a shift in glial metabolism that promotes tissue maintenance and repair.

    What’s even more exciting is that the Rel (NF-κB analog) pathway signals through and activates a TGF-β-like analog, promoting cell survival. This result hints at an evolutionary basis for control of a glial phenotype that maintains homeostasis and repair. While the authors don’t discuss whether peripheral immune cells infiltrate the brain, one nonetheless wonders whether this occurs in their fly models and ultimately impacts neurodegeneration. 

    View all comments by Terrence Town

  2. Mutations in the GRN gene are a common cause of frontotemporal dementia and lead to loss of progranulin (PGRN) protein function, yet the mechanisms leading to neurodegeneration are still unclear. Complete loss of PGRN in mice and humans leads to lysosome dysfunction, a lysosome storage phenotype, which is accompanied by robust neuroinflammation including astrogliosis and microgliosis. Converging evidence from multiple groups suggest that both lysosome dysfunction and inflammation are important components of disease pathogenesis in FTD caused by GRN mutations. Dissecting which cell types in the brain are dysfunctional and/or driving dysfunction is an important remaining question in the field.

    Krabbe et al. performed an elegant set of in vivo and imaging studies to demonstrate OCD-like behavioral alterations (i.e., over-grooming and sociability deficits) in mice lacking progranulin (PGRN) as well as impaired microglia/myeloid cell responses to injury, and medium spiny neuron (MSN) hyperexcitability. To identify the cell type in which Grn deletion mattered, the authors ablated Grn in microglia/myeloid cells and observed increased grooming in mice; conversely, they observed modest reduction in grooming in mice where the master regulator of inflammatory responses (NFκB) was inactivated.

    Next, to interrogate the role of tumor necrosis factor, given that TNF has been implicated in the pathophysiology of FTD and nearly every neurological disorder, the authors crossed Grn KO mice with TNF KO mice. They found that this mitigated the self-grooming modestly and the associated hyperexcitability of MSNs, but not the sociability deficits. Studies from Stellwagen and Malenka almost 10 years ago revealed that glial-derived TNF plays a key role in homeostatic synaptic scaling, a form of synaptic plasticity (Stellwagen and Malenka, 2016). Therefore, excess production of TNF and many other inflammatory mediators may have contributed to disruptions in this form of plasticity and hyperexcitability.

    Overall, Krabbe et al.’s findings reveal a highly dysregulated phenotype of myeloid (microglia) cells in the brain resulting from global ablation of GRN expression. These findings are consistent with those by the recent study by Lui et al., 2016, in which global ablation of Grn was associated with dysregulated microglia/myeloid cells that overproduce inflammatory mediators and over-prune synapses in the thalamus.

    Taken together with other published literature, it is clear that genetic ablation of GRN leads to profound neuroinflammation and alterations in microglia activities. Therefore, it is consistent with how the levels of multiple inflammatory cytokines are altered, which is accompanied by decreased phagocytosis and wound-healing responses.

    While the genetic cross between GRN KO mice and TNF KO mice is an easy way to interrogate the role of TNF and downstream targets in mediating the hyper-inflammatory phenotype, one limitation of this experiment is that the rescue effect may not be the direct result of TNF inhibition alone. Specifically, TNF-deficient mice also lack many other cytokines and chemokines (including IL-6, IL1β, IL-10, IL-12, and CXCL1) (Harms et al., 2012), and the double KO mouse is likely to be missing those, too. As noted by the authors in the conclusions, pharmacological inhibition of TNF or other cytokines would be a more direct way to ascertain its direct role and certainly merits investigation as a potential therapeutic path forward even if PGRN does not directly bind or negatively regulate TNF receptors, as has been reported by three separate and independent laboratories on TNF-TNFR signaling (Chen et al., 2013; Etemadi et al., 2013; Hu et al., 2014). 

    Taken together, this work provides additional evidence that loss of PGRN leads to dysregulation of the lysosome-inflammation axis, paving the way for novel therapeutic strategies for FTD. 

    References:

    Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006 Apr 20;440(7087):1054-9. PubMed.

    Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, Shang Y, Oldham MC, Martens LH, Gao F, Coppola G, Sloan SA, Hsieh CL, Kim CC, Bigio EH, Weintraub S, Mesulam MM, Rademakers R, Mackenzie IR, Seeley WW, Karydas A, Miller BL, Borroni B, Ghidoni R, Farese RV Jr, Paz JT, Barres BA, Huang EJ. Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell. 2016 May 5;165(4):921-35. Epub 2016 Apr 21 PubMed.

    Harms AS, Lee JK, Nguyen TA, Chang J, Ruhn KM, Treviño I, Tansey MG. Regulation of microglia effector functions by tumor necrosis factor signaling. Glia. 2012 Feb;60(2):189-202. Epub 2011 Oct 11 PubMed.

    Chen X, Chang J, Deng Q, Xu J, Nguyen TA, Martens LH, Cenik B, Taylor G, Hudson KF, Chung J, Yu K, Yu P, Herz J, Farese RV, Kukar T, Tansey MG. Progranulin does not bind tumor necrosis factor (TNF) receptors and is not a direct regulator of TNF-dependent signaling or bioactivity in immune or neuronal cells. J Neurosci. 2013 May 22;33(21):9202-13. PubMed.

    Etemadi N, Webb A, Bankovacki A, Silke J, Nachbur U. Progranulin does not inhibit TNF and lymphotoxin-α signalling through TNF receptor 1. Immunol Cell Biol. 2013 Nov-Dec;91(10):661-4. Epub 2013 Oct 8 PubMed.

    Hu Y, Xiao H, Shi T, Oppenheim JJ, Chen X. Progranulin promotes tumour necrosis factor-induced proliferation of suppressive mouse CD4⁺ Foxp3⁺ regulatory T cells. Immunology. 2014 Jun;142(2):193-201. PubMed.

    View all comments by Thomas Kukar

  3. This work is impressive, as it clearly demonstrates that neural NF-κB is a crucial determinant of aging and lifespan in drosophila. The authors’ results are consistent with, and also complementary to, the findings reported from mouse models a few years ago (Zhang et al., 2013). Together with the emergence of many other supportive data for this notion, the case is now strong that the hypothalamic NF-κB pathway has a programmatic role in aging and longevity, even though the responsible types of cells in the brain and especially in the neuroendocrine region of the brain still remain unclear.

    References:

    Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature. 2013 May 1; PubMed.

    View all comments by Dongsheng Cai

  4. By coincidence, Richard Miller and colleagues with the NIA's Interventions Testing Program have just published evidence that interventions that extend natural lifespan in rodents also selectively reduce brain inflammation mediated by TNF-α.

    References:

    Sadagurski M, Cady G, Miller RA. Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner. Aging Cell. 2017 May 20; PubMed.

    View all comments by Michael Rae

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