Recently, Lu Mengze and Zhang Wen, a postdoctoral couple from Weill Cornell Medical College of Cornell University in the United States, published papers on Nature and Cell respectively.
Coincidentally, the two top journal papers were officially accepted and published only one month apart. With children to take care of, their time available for research is very limited.
Even so, they never lost their enthusiasm for scientific research, encouraged and helped each other, and achieved phased research results.
(Source: Lu Mengze, Zhang Wen)
One of the papers revealed that in the process of immune system developing immune tolerance to intestinal flora , type 3 innate lymphocytes (ILC3s, Group 3 Innate Lymphoid Cells) played an important role; another paper reported for the first time that a group of neuronal cells dedicated to sensing pain - nociceptors - play a key role in inhibiting intestinal inflammation and protecting intestinal tissue by regulating the homeostasis of intestinal microbiota.
-type natural lymphocytes promote the establishment of a microbial immune tolerance system in the intestine
Microorganisms colonizing the mammalian intestine can induce inflammatory or inflammatory tolerance T cell (Tregs) responses, but scientists know little about the relevant mechanisms. To this end, researchers have made new explorations into related regulatory mechanisms.
(Source: Nature)
In September 2022, a related paper titled "ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut" was published in Nature [1].
The first authors are Lu Mengze and Hiroaki Suzuki, a visiting scholar at Weill Cornell Medical College, and the corresponding author is Gregory Sonnenberg, associate professor at Weill Cornell Medical College.
Figure | Single-cell RNA sequencing analysis of RORγt+ cells in mouse mesenteric lymph nodes (Source: Nature)
Researchers first used single-cell sequencing to analyze the expression of retinoid-related orphan nuclear receptor γt (RORγt, retinoid-related orphan nuclear) in the mesenteric lymph node (mLN, mesenteric Lymph Node) of healthy mice. receptor γt) immune cell population. The test results of
show that it mainly includes innate immune cells represented by lymphoid tissue inducer-like ILC3s and adaptive immune cells represented by RORγt+Tregs. These cells usually mediate immune responses caused by intestinal microorganisms, thereby maintaining intestinal and body homeostasis.
Researchers further observed through immunofluorescence experiments that ILC3 and RORγt+Treg co-localized in the interfollicular area of mLN, suggesting a possible interaction between the two cells.
Further mouse and in vitro experiments showed that ILC3 can regulate the differentiation of microbial antigen-specific RORγt+Treg cells through major histocompatibility complex class II (MHCII, Major Compatibility Complex II) and integrins.
More importantly, the researchers also used single-cell sequencing technology and flow cytometry to analyze biopsy and resection samples from pediatric inflammatory bowel disease patients and healthy controls.
Figure | ILC3s regulate microbial specific RORγt+ Tregs through MHCII and integrins (Source: Nature)
The results show that ILC3s can promote the differentiation of RORγt+ Tregs and that this regulatory relationship is dysregulated in enteritis patients. This also suggests that ILC3s regulate RORγt+ Tregs and its important role in maintaining healthy intestinal homeostasis in humans.
In summary, this study challenges the traditional concept that dendritic cells are mainly responsible for inducing and promoting the differentiation of regulatory T cells , and proposes a new pathway that ILC3s can regulate intestinal microbial specificity through MHCII and integrins. RORγt+Tregs, and establish normal microbial immune tolerance in the intestine, revealing another important role of ILC3s in maintaining intestinal homeostasis in mice and humans.
This study is not only a theoretical supplement to the immunology textbook, but also provides important theoretical reference and new ideas for the clinical treatment of patients with intestinal diseases.
TRPV1+ Nociceptors regulate intestinal flora
The emergence of human chronic diseases is often accompanied by pain in corresponding tissues and organs, which is regarded as an early warning signal for the emergence of early diseases, especially for intestinal inflammatory diseases.
However, scientists still don’t know whether pain neurons can regulate intestinal flora and intestinal inflammation.
In October 2022, Zhang Wen and her team published a paper in the journal Cell titled "Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection" [2].
They discovered for the first time that TRPV1+ nociceptors, the pain-sensing nerves in the intestine, interact with intestinal flora and play a key role in limiting intestinal inflammation and protecting intestinal tissue. The first author is Zhang Wen, and the corresponding author is David Artis, a professor at Weill Cornell Medical College.
(Source: Cell)
Most inflammatory reactions in the body are accompanied by redness, swelling, heat, pain and dysfunction of local tissues. The body senses physiological pain mediated by adverse external stimuli through a group of nociceptors in the peripheral nervous system.
So, what function does this group of pain receptors have in regulating intestinal inflammation and inflammatory bowel disease ? In order to study this scientific issue, the researchers used neurobiological and chemical genetic methods to specifically regulate the activity and function of TRPV1+Nociceptor, combined with the mouse enteritis injury model, and found that after inhibiting the activity and function of Nociceptor, the susceptibility of mice to enteritis injury was significantly increased.
Furthermore, mice lacking Nociceptor also had increased susceptibility to enteritis damage after permanently depleting TRPV1+Nociceptor using a natural chemical called resinatoxin.
These data demonstrate that TRPV1+Nociceptor has a critical tissue protective function in a mouse enteritis injury model.
So, how exactly does TRPV1+Nociceptor mediate this tissue protective function? Through a series of immunological analyzes and microbiology high-throughput sequencing studies, the researchers found that the intestinal microbiota of mice lacking Nociceptor had significant changes.
By using germ-free mice and mouse models containing specific bacterial flora, the researchers found that if the intestinal microbiota of Nociceptor-deficient mice was transplanted into germ-free mice, the recipient mice transplanted with the Nociceptor-deficient microbiota also acquired a higher susceptibility to enteritis injury.
By using a series of antibiotics to specifically eliminate different microbial flora, the researchers found that Gram-positive dysbiosis is one of the main reasons why Nociceptor-deficient mice have a higher susceptibility to enteritis damage.
Interestingly, the researchers also saw the same phenotype in a mouse model of a single colony of Clostridium as in specific pathogen-free mice.
These data indicate that TRPV1+Nociceptor can protect intestinal tissue from enteritis caused by external damage by regulating the homeostasis of intestinal flora.
Among them, Gram-positive bacteria and Clostridium are the key target bacteria that may be regulated by this group of nerves.
(Source: Cell)
Reference:
In summary, this study reveals for the first time the new immune regulatory function of TRPV1+Nociceptor as a nociceptor neuron and the key role of neuro-microbial interactions in intestinal immunity and intestinal microbial homeostasis. It also provides important theoretical reference and new ideas for the clinical treatment of patients with intestinal diseases.
1. Lyu M, Suzuki H, Kang L. et al. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. Nature 610, 744–751 (2022). https://doi.org/10.1038/s41586-022-05141-x. Wen Zhang, Mengze Lyu, Nicholas J. Bessman. et al.Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection.
