Periodic Reporting for period 4 - NEIMO (Neuronal regulation of immunity)
Reporting period: 2022-05-01 to 2023-06-30
Neuroimmunology is a growing field in science which fills the gap between the organism’s two mega-systems, the nervous and the immune systems. Surprisingly, this field of research is mostly unidirectional, focused on the effects of the immune system on the brain, while our understanding of how the brain affects immunity is still limited. We do not know how or in what form the information available to the brain, e.g. metabolic status, tissue damage (reported as pain), or mental requirements (“I have an ERC deadline and I can’t get sick”), is transmitted to the immune system. NEIMO was designed to bridge this gap by directly testing how the insula, a brain area that integrates multiple levels of cognitive, emotional and visceral information, affects immunity. In another aim, we examined how the peripheral nervous system (PNS) that acts as a conduit between the brain and the periphery, can mediate these signals to the peripheral immune system.
Our central hypothesis was that the brain, and specifically the insula, can regulate the immune system via the PNS. We defined two objectives based on this hypothesis:
Objective A: To determine how insular activity affects the immune system and the capacity to cope with immune challenges. This objective had three sub-aims:
Aim A1: To establish a causal relationship between insula activity and immune responses.
Aim A2: To identify the neurons in the insula that participate in immune regulation.
Aim A3: To study the insular projections mediating the effects on the immune activity
This objective was expected to introduce a new level of understanding regarding how immune information is integrated by the brain as part of interoception and body homeostasis. This research direction was expected to uncover a novel function of the insula as a central regulator of immunity, and enable us to initiate the search for the potentially topographical representation of the immune system in the brain (an “immunological homunculus”).
Objective B: To characterize the effects of local peripheral innervation on the immune system.
In this objective, we proposed to introduce a new tool to study the effects of local innervation to immune organs on the course of an immune response. The goal was to explore the PNS as a localized system, to study its capacity to deliver targeted messages to specific peripheral sites, and to decipher its communication with these peripheral organs.
This objective had four sub-aims:
Aim B.1: To determine how SNS innervation to the lymph nodes affect the course of an immune response.
Aim B.2: To determine how SNS/PaSNS innervation to the gastrointestinal (GI) system affects gut immune responses.
Aim B.3: To determine whether different firing rates of the sympathetic neurons affect the course of an immune response.
Aim B4: To determine whether and how the effects of the insula are mediated via the PNS.
Pursuing this goal on its own enabled us to uncover how this highly localized and temporally precise arm of the nervous system affects immune processes. The communication between the PNS and the immune system is evident from multiple studies, but the mechanisms underlying these effects are largely unknown, and the therapeutic potential embedded in their characterization is clearly underutilized in the clinic.
Our central hypothesis was that the brain, and specifically the insula, can regulate the immune system via the PNS. We defined two objectives based on this hypothesis:
Objective A: To determine how insular activity affects the immune system and the capacity to cope with immune challenges. This objective had three sub-aims:
Aim A1: To establish a causal relationship between insula activity and immune responses.
Aim A2: To identify the neurons in the insula that participate in immune regulation.
Aim A3: To study the insular projections mediating the effects on the immune activity
This objective was expected to introduce a new level of understanding regarding how immune information is integrated by the brain as part of interoception and body homeostasis. This research direction was expected to uncover a novel function of the insula as a central regulator of immunity, and enable us to initiate the search for the potentially topographical representation of the immune system in the brain (an “immunological homunculus”).
Objective B: To characterize the effects of local peripheral innervation on the immune system.
In this objective, we proposed to introduce a new tool to study the effects of local innervation to immune organs on the course of an immune response. The goal was to explore the PNS as a localized system, to study its capacity to deliver targeted messages to specific peripheral sites, and to decipher its communication with these peripheral organs.
This objective had four sub-aims:
Aim B.1: To determine how SNS innervation to the lymph nodes affect the course of an immune response.
Aim B.2: To determine how SNS/PaSNS innervation to the gastrointestinal (GI) system affects gut immune responses.
Aim B.3: To determine whether different firing rates of the sympathetic neurons affect the course of an immune response.
Aim B4: To determine whether and how the effects of the insula are mediated via the PNS.
Pursuing this goal on its own enabled us to uncover how this highly localized and temporally precise arm of the nervous system affects immune processes. The communication between the PNS and the immune system is evident from multiple studies, but the mechanisms underlying these effects are largely unknown, and the therapeutic potential embedded in their characterization is clearly underutilized in the clinic.
Since the beginning of the project, we were successful in executing both objectives. This effort resulted in two main manuscripts. The first manuscript, which is based on objective 1, demonstrates that neurons in the insula encode immune related information and their activation can induce immune reactions. Using viral tracing strategies, we found that neurons active during peripheral inflammation can directly deliver messages to the peripheral sites and that these effects are mediated via the autonomic nervous system.
The manuscript covering these findings was published in Cell in November 2021: Insular cortex neurons encode and retrieve specific immune responses. Koren et al., 2021, Cell 184, 5902–5915.
This manuscript broadly covers all three Aims of this objective.
The paper was selected as one of the Best Cell Papers for 2022 (https://info.cell.com/best-of-cell-2022(opens in new window)) and was covered by News and Views reports in Cell (Gogolla N, 2021), Nature Reviews Neuroscience (Yates D, 2022), Nature (Brea D et al., 2022), Immunity (Cohen JA et al., 2022), Movement Disorders (Olszewska DA et al., 2022).
Based on the ideas developed in this project, we wrote a perspective paper and a review:
1. Immunoception: Defining brain-regulated immunity, Koren T, Rolls A, 2022. Neuron 110(21):3425-3428
2. Immunoception: the insular cortex perspective. Rolls A, 2023, Cell Mol Immunol.
The second manuscript based on Objective 2 demonstrated that sympathetic innervations to the colon affect the course of a local inflammation by modulating MADCAM1 levels on the endothelial cells. This was a surprising finding since it uncovered a new level by which the brain can control immunity by modulating the gateway to the tissue- the blood vessel. This manuscript broadly covers objective B Aim B.1 and part of Aim B.2
This manuscript was published in Immunity in May 2021: Optogenetic activation of local colonic sympathetic innervations attenuates colitis by limiting immune cell extravasation. Schiller et al., 2021, Immunity 54, 1022–1036.
Based on the ideas developed in this project, we wrote a perspective paper that was published in Nature Reviews in Immunology: Neuronal regulation of immunity: why, how and where? Schiller et al., 2021, Nature Reviews in Immunology 21, 20-36
The manuscript covering these findings was published in Cell in November 2021: Insular cortex neurons encode and retrieve specific immune responses. Koren et al., 2021, Cell 184, 5902–5915.
This manuscript broadly covers all three Aims of this objective.
The paper was selected as one of the Best Cell Papers for 2022 (https://info.cell.com/best-of-cell-2022(opens in new window)) and was covered by News and Views reports in Cell (Gogolla N, 2021), Nature Reviews Neuroscience (Yates D, 2022), Nature (Brea D et al., 2022), Immunity (Cohen JA et al., 2022), Movement Disorders (Olszewska DA et al., 2022).
Based on the ideas developed in this project, we wrote a perspective paper and a review:
1. Immunoception: Defining brain-regulated immunity, Koren T, Rolls A, 2022. Neuron 110(21):3425-3428
2. Immunoception: the insular cortex perspective. Rolls A, 2023, Cell Mol Immunol.
The second manuscript based on Objective 2 demonstrated that sympathetic innervations to the colon affect the course of a local inflammation by modulating MADCAM1 levels on the endothelial cells. This was a surprising finding since it uncovered a new level by which the brain can control immunity by modulating the gateway to the tissue- the blood vessel. This manuscript broadly covers objective B Aim B.1 and part of Aim B.2
This manuscript was published in Immunity in May 2021: Optogenetic activation of local colonic sympathetic innervations attenuates colitis by limiting immune cell extravasation. Schiller et al., 2021, Immunity 54, 1022–1036.
Based on the ideas developed in this project, we wrote a perspective paper that was published in Nature Reviews in Immunology: Neuronal regulation of immunity: why, how and where? Schiller et al., 2021, Nature Reviews in Immunology 21, 20-36
Overall, the new findings established the basis for a new research direction in our laboratory, and hopefully, will shift some of the research in the field. Some evidence for this impact is already seen in the form of a feature article done by Nature about this new research direction introduced by our lab (HOW THE BRAIN CONTROLS SICKNESS AND HEALTH by Diana Kwon, Nature, doi: 10.1038/d41586-023-00509-z).
The first set of findings demonstrates the existence of a memory-like representation with specific neuronal ensembles of immune-related information. This sets the stage to a potential new mechanistic understanding of psychosomatic disorders. In the second set of findings, we describe a new mechanism whereby sympathetic fibers can locally control immune reactions by modulating endothelial cells. This provides a new potential mechanism whereby the brain can locally regulate inflammation.
In a follow-up work that extends beyond the original proposal, we used a combination of whole-brain clearing and viral tracing during peripheral inflammatory paradigms, to study the neuronal representations of immune activity. Preliminary results show specific neuronal circuits change during a peripheral immune response. These findings open avenues for further investigation into the mechanisms underlying these effects and potential therapeutic applications and already led us to uncover two new paths in which the brain can monitor immunity.
Based on these findings, we received a POC grant in which we are now studying targeted insula stimulations as treatment for autoimmune disorders.
Moreover, the findings in this project led us establish several new collaborations to test the feasibility of translating our discoveries in humans including some industry partners (INSITECH).
ity of translating our discoveries in humans including some industry partners (INSITECH).
The first set of findings demonstrates the existence of a memory-like representation with specific neuronal ensembles of immune-related information. This sets the stage to a potential new mechanistic understanding of psychosomatic disorders. In the second set of findings, we describe a new mechanism whereby sympathetic fibers can locally control immune reactions by modulating endothelial cells. This provides a new potential mechanism whereby the brain can locally regulate inflammation.
In a follow-up work that extends beyond the original proposal, we used a combination of whole-brain clearing and viral tracing during peripheral inflammatory paradigms, to study the neuronal representations of immune activity. Preliminary results show specific neuronal circuits change during a peripheral immune response. These findings open avenues for further investigation into the mechanisms underlying these effects and potential therapeutic applications and already led us to uncover two new paths in which the brain can monitor immunity.
Based on these findings, we received a POC grant in which we are now studying targeted insula stimulations as treatment for autoimmune disorders.
Moreover, the findings in this project led us establish several new collaborations to test the feasibility of translating our discoveries in humans including some industry partners (INSITECH).
ity of translating our discoveries in humans including some industry partners (INSITECH).