RIPK3-dependent necroptosis is the primary cause of RIPK1-deficient-induced immunodeficiency
Abstract RIPK1 (receptor-interacting serine/threonine kinase 1) plays a pivotal role in developing the immune system—patients with homozygous loss-of-function mutations of RIPK1 present with immunodeficiency and intestinal inflammation. Here, we reported that RIPK1-deficient rats represented defects of human patients and were certified as a suitable disease model. Knocking outRipk3rather thanCaspase-8nearly completely corrected immunodeficiency disorders, developmental defects, and necroptosis in the thymus of RIPK1-deficient rats. However, inflammatory enteritis was still detected in eitherRipk1/Ripk3-orRipk1/Casp-8-double deficient rats and only rescued inRipk1/Ripk3/Caspase-8-triple deficient rats, suggesting RIPK3 mediated necroptosis and Caspase-8 dependent apoptosis contribute in different part in RIPK1-deficient caused the syndrome. Moreover, RIPK1-deficient rat dermal fibroblasts (RDFs) showed sensitive necroptosis and impaired NF-κB activation, also reported inRIPK1-deficienthuman patients. And pharmacological inhibition of NF-κB activation could sensitize necroptosis of rat cells. Since mutations that damage NF-κB activation could cause immunodeficiency in human patients, it suggested that aberrantly activated necroptosis play a vital role in certain kinds of primary immunodeficiency syndromes and pharmacological inhibition of necroptosis could be a novel therapeutic strategy for those diseases..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 24. Feb. Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liu, Xiaoyan [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.1101/2023.02.22.526137 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI038756048 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI038756048 | ||
| 003 | DE-627 | ||
| 005 | 20230226224722.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 230226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2023.02.22.526137 |2 doi | |
| 035 | |a (DE-627)XBI038756048 | ||
| 035 | |a (biorXiv)10.1101/2023.02.22.526137 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liu, Xiaoyan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a RIPK3-dependent necroptosis is the primary cause of RIPK1-deficient-induced immunodeficiency |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract RIPK1 (receptor-interacting serine/threonine kinase 1) plays a pivotal role in developing the immune system—patients with homozygous loss-of-function mutations of RIPK1 present with immunodeficiency and intestinal inflammation. Here, we reported that RIPK1-deficient rats represented defects of human patients and were certified as a suitable disease model. Knocking outRipk3rather thanCaspase-8nearly completely corrected immunodeficiency disorders, developmental defects, and necroptosis in the thymus of RIPK1-deficient rats. However, inflammatory enteritis was still detected in eitherRipk1/Ripk3-orRipk1/Casp-8-double deficient rats and only rescued inRipk1/Ripk3/Caspase-8-triple deficient rats, suggesting RIPK3 mediated necroptosis and Caspase-8 dependent apoptosis contribute in different part in RIPK1-deficient caused the syndrome. Moreover, RIPK1-deficient rat dermal fibroblasts (RDFs) showed sensitive necroptosis and impaired NF-κB activation, also reported inRIPK1-deficienthuman patients. And pharmacological inhibition of NF-κB activation could sensitize necroptosis of rat cells. Since mutations that damage NF-κB activation could cause immunodeficiency in human patients, it suggested that aberrantly activated necroptosis play a vital role in certain kinds of primary immunodeficiency syndromes and pharmacological inhibition of necroptosis could be a novel therapeutic strategy for those diseases. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Zhu, Xinxin |4 aut | |
| 700 | 1 | |a Shu, Zhaoqian |4 aut | |
| 700 | 1 | |a Sun, Liming |4 aut | |
| 700 | 1 | |a Wang, Huayi |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2023) vom: 24. Feb. |
| 773 | 1 | 8 | |g year:2023 |g day:24 |g month:02 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2023.02.22.526137 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 24 |c 02 | ||