Nicholas Arpaia, Ph.D.

Associate Professor of Microbiology & Immunology
Ph.D., University of California, Berkeley

Mucosal immunity, tissue repair, immunometabolism, host-microbe interactions

Research
Mounting an immune response is an energetically costly endeavor, with the potential to greatly impact host fitness. A cost-benefit relationship — between the collateral damage associated with an inflammatory response and the benefit of inflammation in protecting the host from infection — imparts a selective pressure that ensures the magnitude of a response is proportional to the potential threat encountered. To achieve homeostasis, the immune system must balance pro- and anti-inflammatory responses to neutralize invading pathogens while limiting or preventing damage to surrounding tissue. At mucosal barriers — which are colonized by diverse communities of commensal microbes and serve to interface the internal physiology of an organism with the ever-changing external environment — fine-tuning opposing immune responses is of even greater relevance. Constant exposure to novel environmental antigens and high concentrations of microbial ligands that can activate innate immune receptors increase the risk for persistent inflammatory activation. As a result, complex immune networks operate to contextualize diverse microbial and environmental stimuli. These inputs subsequently shape mucosal immune responses and synergize to preserve mucosal barrier integrity and function. Consequently, aberrant immune responses, due to a breakdown in tolerance or defects in barrier maintenance, largely underlie the etiology of chronic mucosal inflammatory disorders, including Crohn's disease and ulcerative colitis.

Our laboratory is interested in understanding how mucosal immune responses are coordinated to maintain homeostasis and respond to microbial infection, barrier disruption, or alterations in commensal microbial diversity — with an emphasis on how these molecular decisions are balanced within the context of host fitness and organ physiology. Our studies are geared toward uncovering pathways with the potential for therapeutic manipulation, specifically focusing on the signals that drive pro- and anti-inflammatory immune responses within each setting. Deciphering the molecular inputs that drive these opposing fates, and the subsequent cellular and molecular signals that immune cells employ, has applications in the treatment of infectious disease, cancer and autoimmune disorders.

For more information, visit our lab website.

Selected Publications

1. Savage, T. M., Fortson, K. T., de Los Santos-Alexis, K., Oliveras-Alsina, A., Rouanne, M., Rae, S. S., Gamarra, J. R., Shayya, H., Kornberg, A., Cavero, R., Li, F., Han, A., Haeusler, R. A., Adam, J., Schwabe, R. F. and Arpaia, N. (2024) Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis. Immunity 57: 303–318.e6. https://doi.org/10.1016/j.immuni.2024.01.009

2. Vincent, R.L., Gurbatri, C.R., Li, F., Vardoshvili, A., Coker, C., Im, J., Ballister, E.R., Rouanne, M., Savage, T., de Los Santos-Alexis, K., Redenti, A., Brockmann, L., Komaranchath, M., Arpaia, N. and Danino, T. (2023) Probiotic-guided CAR-T cells for solid tumor targeting. Science 382: 211-218. https://doi.org/10.1126/science.add7034

3. Savage, T.M., Vincent, R.L, Rae, S.S., Huang, L.H., Ahn, A., Pu, K., Li, F., Santos-Alexis, K.L., Coker, C., Danino, T. and Arpaia, N. (2023) Chemokines expressed by engineered bacteria recruit and orchestrate antitumor immunity. Science Advances 9: eadc9436. https://doi.org/10.1126/sciadv.adc9436

4. Rankin, L.C., Kaiser, K.A., Santos-Alexis, K.L., Park, H., Uhlemann, A.C., Gray, D.H.D. and Arpaia, N. (2023) Dietary tryptophan deficiency promotes gut RORγt+Treg cells at the expense of Gata3+ Treg cells and alters commensal microbiota metabolism. Cell Reports 42: 112135. Advance online publication. https://doi.org/10.1016/j.celrep.2023.112135

5. Kaiser, K.A., Loffredo, L.F., Santos-Alexis, K.L., Ringham, O.R. and Arpaia, N. (2023) Regulation of the alveolar regenerative niche by amphiregulin-producing regulatory T cells. The Journal of Experimental Medicine 220: e20221462. https://doi.org/10.1084/jem.20221462 (Cover article)

6. Gurbatri, C.R., Arpaia, N. and Danino, T. (2022) Engineering bacteria as interactive cancer therapies. Science 378: 858–864. https://doi.org/10.1126/science.add9667

7. Filliol, A., Saito, Y., Nair, A., Dapito, D.H., Yu, L.X., Ravichandra, A., Bhattacharjee, S., Affo, S., Fujiwara, N., Su, H., Sun, Q., Savage, T.M., Wilson-Kanamori, J.R., Caviglia, J.M., Chin, L., Chen, D., Wang, X., Caruso, S., Kang, J. K., Amin, A.D., Wallace, S., Dobie, R., Yin, D., Rodriguez-Fiallos, O.M., Yin, C., Mehal, A., Izar, B., Friedman, R.A., Wells, R.G., Pajvani, U.B., Hoshida, Y., Remotti, H.E., Arpaia, N., Zucman-Rossi, J., Karin, M., Henderson, N.C., Tabas, I. and Schwabe, R.F. (2022) Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610: 356–365. https://doi.org/10.1038/s41586-022-05289-6

8. Harimoto, T., Hahn, J., Chen, Y.Y., Im, J., Zhang, J., Hou, N., Li, F., Coker, C., Gray, K., Harr, N., Chowdhury, S., Pu, K., Nimura, C., Arpaia, N., Leong, K.W. and Danino, T. (2022) A programmable encapsulation system improves delivery of therapeutic bacteria in mice. Nature Biotechnology 40: 1259–1269. https://doi.org/10.1038/s41587-022-01244-y

9. Affo, S., Nair, A., Brundu, F., Ravichandra, A., Bhattacharjee, S., Matsuda, M., Chin, L., Filliol, A., Wen, W., Song, X., Decker, A., Worley, J., Caviglia, J.M., Yu, L., Yin, D., Saito, Y., Savage, T., Wells, R.G., Mack, M., Zender, L., Arpaia, N., Remotti, H.E., Rabadan, R., Sims, P., Leblond, A.L., Weber, A., Riener, M.O., Stockwell, B.R., Gaublomme, J., Llovet, J.M., Kalluri, R., Michalopoulos, G.K., Seki, E., Sia, D., Chen, X., Califano, A. and Schwabe, R.F. (2021) Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 39: 866–882.e11. https://doi.org/10.1016/j.ccell.2021.03.012

10. Rouanne, M., Arpaia, N. and Marabelle, A. (2021) CXCL13 shapes tertiary lymphoid structures and promotes response to immunotherapy in bladder cancer. European Journal of Cancer 151: 245–248. https://doi.org/10.1016/j.ejca.2021.03.054

11. Gurbatri, C. R., Lia, I., Vincent, R., Coker, C., Castro, S., Treuting, P. M., Hinchliffe, T. E., Arpaia, N. and Danino, T. (2020) Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies. Science Translational Medicine 12: eaax0876. https://doi.org/10.1126/scitranslmed.aax0876

12. Chowdhury, S., Castro, S., Coker, C., Hinchliffe, T.E., Arpaia, N.* and Danino, T.* (2019) Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nature Medicine 25: 1057-1063. https://doi.org/10.1038/s41591-019-0498-z *Co-corresponding

13. Kaiser, K.A. and Arpaia, N. (2018) Glycans for good. Science Immunol. 3: eaav1041.

14. Rankin, L.C. and Arpaia, N. (2018) Treg cells: A LAGging hand holds the double-edged sword of the IL-23 axis. Immunity 49: 201-203.

15. Yen, B., Fortson, K.T., Rothman, N.J., Arpaia, N.* and Reiner, S.L.* (2018) Clonal bifurcation of Foxp3 expression visualized in thymocytes and T cells. Immunohorizons 2: 119-128. *Co-corresponding

16. Green, J.A.*, Arpaia, N.*, Schizas, M., Dobrin, A. and Rudensky, A.Y. (2017) A nonimmune function of T cells in promoting lung tumor progression. J. Exp. Med. 214: 3565. *Co-equal

17. Arpaia, N., Green, J.A., Moltedo, B., Arvey, A., Hemmers, S., Yuan, S., Treuting, P.M. and Rudensky, A.Y. (2015) A distinct function of regulatory T cells in tissue protection. Cell 162: 1078-1089.

18. Jenq, R.R., Taur, Y., Devlin, S.M., Ponce, D.M., Goldberg, J.D., Ahr, K.F., Littmann, E.R., Ling, L., Gobourne, A.C., Miller, L.C., Docampo, M.D., Peled, J.U., Arpaia, N., Cross, J.R., Peets, T.K., Lumish, M.A., Shono, Y., Dudakov, J.A., Poeck, H., Hanash, A.M., Barker, J.N., Perales, M.A., Giralt, S.A., Pamer, E.G. and van den Brink M.R. (2015) Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biol. Blood Marrow Transplant. 21: 1373-1383.

19. Arpaia, N. (2014) Keeping peace with the microbiome: acetate dampens inflammatory cytokine production in intestinal epithelial cells. Immunol. Cell Biol. 92: 561-562.

20. Sivick, K.E., Arpaia, N., Shu, J. and Barton, G.M. (2014) Toll-like receptor deficient mice reveal how innate immune signaling influences Salmonella virulence strategies. Cell Host and Microbe 15: 203-213.

21. Arpaia, N. and Rudensky, A.Y. (2014) Microbial metabolites control gut inflammatory responses. Proc. Natl. Acad. Sci. U.S.A. 111: 2058-2059.

22. Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J.R., Pfeffer, K., Coffer, P.J. and Rudensky, A.Y. (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504: 451-455.

23. Arpaia, N. and Barton, G.M. (2013) The impact of Toll-like receptors on bacterial virulence strategies. Curr. Opin. Microbiol. 16: 17-22.

24. Mouchess, M.L., Arpaia, N., Souza, G., Barbalat, R., Ewald, S.E., Lau, L. and Barton, G.M. (2011) Transmembrane mutations in toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation. Immunity 35: 1-12.

25. Arpaia, N. and Barton, G.M. (2011) Toll-like receptors: key players in antiviral immunity. Curr. Opin. Virol. 1: 1-8.

26. Arpaia, N., Godec, J., Lau, L., Sivick, K.E., McLaughlin, L.M., Jones, M.B., Dracheva, T., Peterson, S.N., Monack, D.M. and Barton, G.M. (2011) TLR signaling is required for Salmonella typhimurium virulence. Cell 144: 675-688.