Immunology Faculty Member - Isaac Chiu, PhD

Isaac Chiu, PhD

Harvard Medical School
NRB Building, Room 830
77 Avenue Louis Pasteur
Boston, MA 02115
Email: isaac_chiu@hms.harvard.edu
Visit my lab page here.



Our goal is to understand the role of neuro-immune interactions in host defense and inflammation. The peripheral nervous system densely innervates barrier tissues including the skin, the gastrointestinal tract, and respiratory tract. Pain and stress affect the immune response against pathogens, but the underlying molecular and cellular mechanisms are not well understood. We have found that peripheral sensory neurons sense microbes to produce pain, and regulate the immune response during inflammation.

Neural-immune interactions in host defense and immunity
It is increasingly clear that the nervous system plays a powerful role in regulating the immune system during inflammation. We recently found that sensory neurons play a key role in regulating bacterial host defense. Sensory neurons release neuropeptides (e.g. CGRP, SP, or VIP) which act on their cognate receptors on immune cells to modulate immune function. Sympathetic neurons release norepinephrine which acts on adrenergic receptors expressed by immune cells. We are now investigating the role of these neuro-immune interactions in the skin, gut, and respiratory tract. We aim to use targeted genetic and pharmacological tools to ascertain the role of these neuro-immune interactions in host defense against pathogens and in tissue inflammation. We are also investigating if neurons play a role in driving inflammatory diseases at barrier tissues such as the GI tract, respiratory tract, and skin.

Neuronal sensing of bacteria in infection and pain.

Pain is a component of many infectious diseases, including bacterial and viral infection. We have found that nociceptor sensory neurons are directly activated by bacterial pathogens and their secreted factors produce pain. We have found that different types of gut-commensal microbes are able to directly induce calcium influx in DRG sensory neurons. The gut-brain-axis could be involved in regulating pain. We are identifying the key molecular mechanisms by which different types of microbes and pathogens induce neuronal activation. Isolation of microbe-derived neuromodulatory factors could lead to new treatments for chronic pain and infectious diseases.

Neural-immune cross-talk in pain and itch.

Nociceptors and pruriceptors are the specific subsets of sensory neurons that produce pain and itch, respectively. However, the mechanisms leading to chronic pain or itch are not well understood. Atopic dermatitis is a skin disease characterized by chronic itch. Chronic neuropathic pain is a widespread condition where there are few effective treatments. Sensory neurons express receptors for specific immune derived factors, including interleukins and lipid mediators. We are investigating how specific immune signaling mechanisms may drive chronic itch or chronic pain.



Last Update: 4/11/2018



Publications

Baral P, Umans BD, Li L, Wallrapp A, Bist M, Kirschbaum T, Wei Y, Zhou Y, Kuchroo VK, Burkett PR, Yipp BG, Liberles SD, and Chiu IMNociceptor sensory neurons suppress neutrophil and gd T cell responses in bacterial lung infections and lethal pneumonia.Nature Medicine. 2018 Mar 5. DOI: 10.1038/nm.4501.

Blake KJ, Baral P, Voisin T, Lubkin A, Pinho-Ribeiro FA, Adams KL, Roberson DP, Ma YC, Otto M, Woolf CJ, Torres VJ, and Chiu IMStaphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nature Communications. 2018 Jan 2;9(1):37. DOI: 10.1038/s41467-017-02448-6.

Wallrapp A*, Riesenfeld SJ*, Burkett PR*, Abdulnour RE, Nyman J, Dionne D, Hofree M, Cuoco MS, Rodman C, Farouq D, Haas BJ, Tickle TL, Trombetta JJ, Baral P, Klose CSN, Mahlakoiv T, Artis D, Rozenblatt-Rosen O, Chiu IM, Levy BD, Kowalczyk MS, Regev A, and Kuchroo VK. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature. 2017 Sep 21;549(7672):351-356. DOI: 10.1038/nature24029. *Equal contributions.

Yissachar N, Zhou Y, Ung L, Lai NY, Mohan JF, Ehrlicher A, Weitz DA, Kasper DL, 
Chiu IM‡, Mathis D, and Benoist CAn intestinal organ culture system uncovers a role for the nervous system in microbe-immune crosstalk. Cell. 2017 Mar 9;168(6):1135-1148.e12. DOI: 10.1016/j.cell.2017.02.009Co-corresponding authors.

Talbot S, Abdulnour RE, Burkett PR, Lee S, Cronin SJ, Pascal MA, Laedermann C, Foster SL, Tran JV, Lai N, Chiu IM, Ghasemlou N, DiBiase M, Roberson D, Von Hehn C, Agac B, Haworth O, Seki H, Penninger JM, Kuchroo VK, Bean BP, Levy BD, and Woolf CJ. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron. 2015 Jul 15;87(2):341-54. DOI: 10.1016/j.neuron.2015.06.007.

Ghasemlou N, Chiu IM, Julien JP, and Woolf CJ. CD11b+Ly6G- myeloid cells mediate mechanical inflammatory pain hypersensitivity. Proceedings of National Academy Sciences USA. 2015 Dec 8;112(49):E6808-17. DOI: 10.1073/pnas.1501372112.

Wainger BJ, Buttermore ED, Oliveira JT, Mellin C, Lee S, Saber WA, Wang AJ, Ichida JK, Chiu IM, Barrett L, Huebner EA, Bilgin C, Tsujimoto N, Brenneis C, Kapur K, Rubin LL, Eggan K, and Woolf CJ. Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts. Nature Neuroscience. 2015 Jan;18(1):17-24. DOI: 10.1038/nn.3886.

Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, Wainger B, Strominger A, Muralidharan S, Horswill AR, Bubeck Wardenburg J, Hwang SW, Carroll MC, and Woolf CJ. Bacteria activate sensory neurons that modulate pain and inflammation. Nature. 2013 Sep 5; 501(7465):52-7. DOI: 10.1038/nature12479.

Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O'Keeffe S, Phatnani HP, Muratet M, Carroll MC, Levy S, Tavazoie S, Myers RM, and Maniatis T. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an Amyotrophic Lateral Sclerosis mouse model. Cell Reports. 2013 Jul 25; 4(2):385-401. DOI: 10.1016/j.celrep.2013.06.018.

Chiu IM, Phatnani H, Kuligowski M, Tapia JC, Carrasco MA, Zhang M, Maniatis T, and Carroll MC. Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proceedings of National Academy Sciences USA. 2009 Dec 8; 106(49):20960-5.

Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, Brown RH, and Carroll MC. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proceedings of National Academy Sciences USA. 2008 Nov 18; 105(46):17913-8.



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