John Lukens, Ph.D.
B.S., 2003 University of Richmond
Ph.D., 2008 University of Virginia
Postdoctoral Research, 2008-2014, St. Jude Children’s Research Hospital
Our laboratory is focused on understanding how immunological pathways contribute to neurodegenerative, neurodevelopmental, mental and behavior disorders. We are actively investigating the cellular and molecular pathways that contribute to neuroinflammation and central nervous system (CNS)-related tissue damage. We are particularly interested in elucidating the mechanisms that regulate inflammatory cytokine production in the CNS in response to both tissue injury and CNS infection. To this end, we utilize models of multiple sclerosis, CNS injury, neurodegenerative disease, autism spectrum disorder and CNS infection to identify the cell types and molecular pathways that are responsible for neuroinflammation. Our previous work has identified IL-1-dependent signaling as a critical regulator of inflammatory cytokine production and tissue destruction in a model of multiple sclerosis. Future work in our laboratory will focus on further characterizing the immunological signaling pathways that control neuroinflammation in models of neurodegeneration, CNS injury and CNS infection.
We are also exploring how modulation of the microbial landscape in the intestine influences the development of CNS disorders. Emerging data suggests that crosstalk between the intestinal microbiome (collection of trillions of microbes that peacefully live within us) and the brain is a pivotal regulator of many CNS diseases; however the mechanisms by which the microbiome can influence CNS disease pathogenesis remain poorly defined. In our lab we are investigating how microbiota-dependent control of immune responses specifically influences neurological disease pathogenesis, CNS function and mental health.
Effective treatment strategies are desperately needed for most CNS diseases including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), CNS injury, autism and various forms of CNS infectious disease. Perturbations in immune responses are widely believed to centrally contribute to the pathogenesis of many, if not all, neurological disorders. In the Lukens laboratory we believe that a more complete characterization of the interactions between the immune and nervous systems will lead to improved understanding of complex neurological disorders in humans and will help to identify novel and promising therapeutic targets to treat CNS diseases.
(1) Roles and regulation of IL-1 family cytokines in neurodegenerative disorders and CNS injury.
(2) Control of demyelinating neuroinflammation by innate immune sensors.
(3) Investigation of how microbiome-dependent regulation of immune re ponses influences cognition, behavior, mental health and neurodegenerative disease.
(4) Regulation of glia cell function by inflammatory caspases.
(5) Identification of the innate signaling pathways that are required to mount protective immune responses against CNS pathogens.
Gadani SP, Walsh JT, Lukens JR*, Kipnis J*. Dealing with danger in the CNS: The response of the immune system to injury. Neuron. 2015 Jul 1;87(1):47-62. * Co-corresponding author
Lukens JR, Gurung P, Shaw PJ, Barr MJ, Zaki MH, Brown SA, Vogel P, Chi H, Kanneganti TD. The NLRP12 sensor negatively regulates autoinflammatory disease by modulating interleukin-4 production in T cells. Immunity. 2015 Apr 21;42(4):654-64.
Walsh JT, Hendrix S, Boato F, Smirnov I, Zheng J, Lukens JR, Gadani S, Hechler D, Gölz G, Rosenberger K, Kammertöns T, Vogt J, Vogelaar C, Siffrin V, Radjavi A, Fernandez-Castaneda A, Gaultier A, Gold R, Kanneganti TD, Nitsch R, Zipp F, Kipnis J. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. J Clin Invest. 2015 Feb;125(2):699-714.
Gurung P, Lukens JR, Kanneganti TD. Mitochondria: diversity in the regulation of the NLRP3 inflammasome. Trends Mol Med. 2015 Mar;21(3):193-201.
Lukens JR, Gurung P, Vogel P, Johnson RG, Carter RA, McGoldrick DJ, Bandi SR, Calabrese CR, Vande Walle L, Lamkanfi M, Kanneganti TD. Dietary modulation of the microbiome affects autoinflammatory disease. Nature. DOI: 10.1038/nature13788. PMID:25274309.
Lukens JR, Kanneganti TD. Beyond canonical inflammasomes: emerging pathways in IL-1-mediated autoinflammatory disease. Seminars in Immunopathology. 2014. Sep;36(5):595-609.
Lukens JR, Gross JM, Calabrese CR, Iwakura Y, Lamkanfi M, Vogel P, Kanneganti TD. Critical role for inflammasome-independent IL-1b production in osteomyelitis. PNAS. 2014 Jan 21;111(3):1066-71.
Lukens JR, Kanneganti TD. SHP-1 and IL-1a conspire to provoke neutrophilic dermatoses. Rare Diseases. 2014 Jan; 2(1): 1-5 e27742. doi: 10.4161/rdis.27742.
Weinlich R, Oberst A, Dillon CP, Janke LJ, Milasta S, Lukens JR, Rodriguez DA, Gurung P, Savage C, Kanneganti TD, Green DR. Protective Roles for Caspase-8 and cFLIP in Adult Homeostasis. Cell Reports. 2013 Oct 2. doi:pii: S2211-1247(13)00505-6.
Lukens JR, Vogel P, Johnson GR, Kelliher MA, Iwakura Y, Lamkanfi M, Kanneganti TD. RIP1-driven autoinflammation targets IL-1a independently of inflammasomes and RIP3. Nature. 2013 Jun 13;498(7453):224-7.
Lukens JR, Gross JM, Kanneganti TD. IL-1 family cytokines trigger sterile inflammatory disease. Front Immunol. 2012;3:315.
Lukens JR, Kanneganti TD. Fat chance: not much against NKT cells. Immunity. 2012 Sep 21;37(3):447-9.
Anand PK, Malireddi RK, Lukens JR, Vogel P, Bertin J, Lamkanfi M, Kanneganti TD. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature. 2012 Aug 16;488(7411):389-93.
Lukens JR, Barr MJ, Chaplin DD, Chi H, Kanneganti TD. Inflammasome-derived IL-1b and the IL-1R1/MYD88 signaling axis regulate the production of GM-CSF by CD4+ T cells and γδ T cells. J Immunol. 2012 Apr 1;188(7):3107-15. *JI Author Choice Article.
Lukens JR, Dixit VD, Kanneganti TD. Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. Discovery Medicine. 2011 Jul;12(62):65-74.
Shaw PJ, Barr MJ, Lukens JR, McGargill MA, Chi H, Mak TW, Kanneganti TD. Signaling via the RIP2 adaptor protein in central nervous system-infiltrating dendritic cells promotes inflammation and autoimmunity. Immunity. 2011 Jan 28;34(1):75-84.
Shaw PJ, Lukens JR, Burns S, Chi H, McGargill MA, Kanneganti TD. Cutting edge: Critical role for PYCARD/ASC in the development of experimental autoimmune encephalomyelitis. J Immunol. 184(9):4610-4614, 2010.
Lassen MG, Lukens JR, Dolina JS, Brown MG, Hahn YS. Intrahepatic IL-10 maintains NKG2A+Ly49- liver NK cells in a functionally hyporesponsive state. J Immunol. 184(5):2693-2701, 2010.
Lukens JR, Dolina JS, Kim TS, Tacke RS, Hahn YS. Liver is able to activate naïve CD8+ T cells with dysfunctional anti-viral activity in the murine system. PLoS One. 4(10):e7619, 2009.
Lukens JR, Cruise MW, Lassen MG, Hahn YS. Blockade of PD-1/B7-H1 interaction restores effector CD8+ T cell responses in a hepatitis C virus core murine model. J Immunol. 180(7):4875-4884, 2008.
Hwang ML, Lukens JR, Bullock TN. Cognate memory CD4+ T cells generated with dendritic cell priming influence the expansion, trafficking, and differentiation of secondary CD8+ T cells and enhance tumor control. J Immunol. 179(9):5829-5838, 2007.
Cruise MW, Lukens JR, Nguyen AP, Lassen MG, Waggoner SN, Hahn YS. Fas ligand is responsible for CXCR3 chemokine induction in CD4+ T cell-dependent liver damage. J Immunol. 176(10):6235-6244, 2006.
Cruise MW, Lukens JR, Hahn YS. Hepatitis C virus’s immune evasion strategies. Curr Immunol Rev. 1(3):223-236, 2005.
Holub JM, O’Toole-Colin K, Getzel A, Argenti A, Evans MA, Smith DC, Dalglish GA, Rifat S, Wilson DL, Taylor BM, Miott U, Glersaye J, Lam KS, McCranor BJ, Berkowitz JD, Miller RB, Lukens JR, Krumpe K, Gupton JT, Burnham BS. Lipid-lowering effects of ethyl 2-phenacyl-3-aryl-1H-pyrrole- 4-carboxylates in rodents. Molecules. 9(3):134-157, 2004.
Gupton J, Clough S, Miller R, Lukens J, Henry C, Kanters R, Sikorski J. The application of vinylogous iminium salt derivatives to the synthesis of ningalin B hexamethyl ether. Tetrahedron. 59:207-215, 2003.
John Lukens, Ph.D.
Department of Neuroscience
Center for Brain Immunology and Glia
University of Virginia
409 Lane Road, MR4- 6102
Charlottesville VA 22908