Current Perspectives on the Role of TNF inHematopoiesis Using Mice With Humanization of TNF/LT System.

Violetta S Gogoleva,Taisiya R Yurakova,Kamar-Sulu N Atretkhany,Sergei A Nedospasov,Arina P Dygay,Marina S Drutskaya

doi:10.3389/fimmu.2021.661900

Abstract

TNF is a multifunctional cytokine with its key functions attributed to inflammation, secondary lymphoid tissue organogenesis and immune regulation. However, it is also a physiological regulator of hematopoiesis and is involved in development and homeostatic maintenance of various organs and tissues. Somewhat unexpectedly, the most important practical application of TNF biology in medicine is anti-TNF therapy in several autoimmune diseases. With increased number of patients undergoing treatment with TNF inhibitors and concerns regarding possible adverse effects of systemic cytokine blockade, the interest in using humanized mouse models to study the efficacy and safety of TNF-targeting biologics in vivo is justified. This Perspective discusses the main functions of TNF and its two receptors, TNFR1 and TNFR2, in steady state, as well as in emergency hematopoiesis. It also provides a comparative overview of existing mouse lines with humanization of TNF/TNFR system. These genetically engineered mice allow us to study TNF signaling cascades in the hematopoietic compartment in the context of various experimental disease models and for evaluating the effects of various human TNF inhibitors on hematopoiesis and other physiological processes.

Highlights

TO HEMATOPOIESISHematopoiesis is the process of blood cell development that in vertebrates is initiated early during embryogenesis and may be divided into 3 phases or so-called distinct waves of hematopoiesis.The first wave takes place in the yolk sac starting in mice at embryonic day 7.5 (E7.5) and generates unipotent blood cell types [1]
The third wave of hematopoiesis represents definitive hematopoiesis and is dependent on the activity of hematopoietic stem cells (HSCs), which are the basic units of the adult hematopoietic system
HSCs generated in the embryonic aorta-gonad-mesonephros region first colonize the fetal liver (E10.5) and shortly before birth (E16) migrate to the bone marrow (BM), where the majority of HSCs reside to sustain steady state hematopoiesis [3]

Summary

Introduction

TO HEMATOPOIESISHematopoiesis is the process of blood cell development that in vertebrates is initiated early during embryogenesis and may be divided into 3 phases or so-called distinct waves of hematopoiesis.The first (or primitive) wave takes place in the yolk sac starting in mice at embryonic day 7.5 (E7.5) and generates unipotent blood cell types [1]. Treatment of rheumatoid arthritis and inflammatory bowel disease (IBD) patients with Etanercept or Infliximab, respectively, led to formation of cutaneous and systemic T-cell lymphomas [75].

Results

Conclusion