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Biology subjects

Thorp, M.

Publications and source records attributed to Thorp, M..

2 recordsLinked to original sources
bioRxiv2023

Myeloid A20 is critical for type-2 immune mediated helminth resistance

Protective immunity against intestinal helminths requires induction of robust Type-2 immunity orchestrated by various cellular and soluble effectors which promote goblet cell hyperplasia, mucus production, epithelial proliferation and smooth muscle contractions to expel worms and reestablish immune homeostasis. Conversely, defects in type-2 immunity result in ineffective helminth clearance, persistent infection and chronic inflammation. We identify A20 as an essential myeloid factor for the induction of type-2 immune responses against the intestinal parasite Trichuris muris. Myeloid cell-specific loss of A20 in mice (A20myel-KO) results in chronic Trichuris muris infection and intestinal inflammation. Myeloid A20 deficient mice are not able to induce anti-helmith type-2 immune responses while instead mount detrimental Th1/Th17 polarized immune responses. Antibody-mediated neutralization of the type-1 cytokines IFN{gamma}, IL18 and IL12 prevents Th1/Th17 polarization and reestablishes Type-2 mediated protective immunity against Trichuris muris in A20myel-KO mice. In contrast, the strong Th1/Th17 biased immunity in A20myel-KO mice offers protection against Salmonella infection. We hereby identify A20 as an essential myeloid factor to initiate approriate adaptive immunity in response to infection, and to induce a balanced type-2 immune response against the intestinal parasite Trichuris muris. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/556360v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@632052org.highwire.dtl.DTLVardef@1def1f2org.highwire.dtl.DTLVardef@1de8459org.highwire.dtl.DTLVardef@1c316ff_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstractThe clearance of gastrointestinal helmiths depends on type-2 immunity. Helminths interact with and damage intestinal tissue, which leads to the release of intracellular DAMPs and cytokines such as TSLP and IL33, and IL25 produced by epithelial cells. These factors may activate myeloid cells and ILCs, which further activate T and B cells to mount effective Th2 responses and the secretion of IL4, IL5 and IL13 cytokines, as well as helminth-specific IgG1 immunoglobulins, leading to effective expulsion of the helminths. Deletion of A20 in the myeloid cells leads to enhanced secretion of type-1 cytokines, including IL12, IL18 and IFN{gamma}, which impede type-2 immune-mediated helminth clearance and promotes chronic intestinal inflammation.

immunology↗
bioRxiv2023

Sterile triggers drive joint inflammation in TNF and IL-1beta dependent mouse arthritis models

Arthritis is the most common extra-intestinal complication in inflammatory bowel disease (IBD). Conversely, arthritis patients are at risk for developing IBD and often display subclinical gut inflammation. These observations suggest a shared disease etiology, commonly termed the gut-joint-axis. The clinical association between gut and joint inflammation is further supported by the success of common therapeutic strategies and microbiota dysbiosis in both conditions. Most data however support a correlative relationship between gut & joint inflammation, while causative evidence is lacking. Using two independent transgenic mouse arthritis models, either TNF or IL1{beta} dependent, we demonstrate that arthritis develops independently of the microbiota and intestinal inflammation, since both lines develop full-blown articular inflammation under germ-free conditions. In contrast, TNF-driven gut inflammation is fully rescued in germ-free conditions indicating that the microbiota is driving TNF-induced gut inflammation. Together, our study demonstrates that, although common inflammatory pathways may drive both gut and joint inflammation, the molecular triggers initiating such pathways are distinct in these tissues.

immunology↗