TNFAIP3 Deficiency Affects Monocytes, Monocytes-Derived Cells and Microglia in Mice.

Francesca Montarolo,Carlotta Tessarolo,Serena Martire,Simona Perga,Michela Spadaro,Antonio Bertolotto

doi:10.3390/ijms21082830

Abstract

The intracellular-ubiquitin-ending-enzyme tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is a potent inhibitor of the pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB) pathway. Single nucleotide polymorphisms in TNFAIP3 locus have been associated to autoimmune inflammatory disorders, including Multiple Sclerosis (MS). Previously, we reported a TNFAIP3 down-regulated gene expression level in blood and specifically in monocytes obtained from treatment-naïve MS patients compared to healthy controls (HC). Myeloid cells exert a key role in the pathogenesis of MS. Here we evaluated the effect of specific TNFAIP3 deficiency in myeloid cells including monocytes, monocyte-derived cells (M-MDC) and microglia analyzing lymphoid organs and microglia of mice. TNFAIP3 deletion is induced using conditional knock-out mice for myeloid lineage. Flow-cytometry and histological procedures were applied to assess the immune cell populations of spleen, lymph nodes and bone marrow and microglial cell density in the central nervous system (CNS), respectively. We found that TNFAIP3 deletion in myeloid cells induces a reduction in body weight, a decrease in the number of M-MDC and of common monocyte and granulocyte precursor cells (CMGPs). We also reported that the lack of TNFAIP3 in myeloid cells induces an increase in microglial cell density. The results suggest that TNFAIP3 in myeloid cells critically controls the development of M-MDC in lymphoid organ and of microglia in the CNS.

Highlights

Inflammation is an adaptive physiological response to cell injury characterized by the production of pro- and anti-inflammatory mediators that establish both innate and acquired immune response [1]
We demonstrated a negative correlation between the tumor necrosis factor alpha-induced protein 3 (TNFAIP3) gene expression level and the clinical parameters such as the relapse rate and Expanded Disability Status Scale (EDSS) score, indicating that the most aggressive forms of Multiple Sclerosis (MS) are characterized by lower level of TNFAIP3 expression [13]
To characterize the phenotype of adult TNFAIP3cx3cr1-KO mice, their body weight was recorded at 3 months of age

Summary

Introduction

Inflammation is an adaptive physiological response to cell injury characterized by the production of pro- and anti-inflammatory mediators that establish both innate and acquired immune response [1]. Many signaling molecules produced by inflammatory events are under the control of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), able to induce inflammatory responses through the activation and the production of pro-inflammatory cytokines, cellular mediators and response genes [2]. In this context, the intracellular-ubiquitin-ending-enzyme tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is one of the most potent inhibitor of the NF-kB pathway [3]. TNFAIP3 appears to be a dual function enzyme that adds and subtracts ubiquitin moieties to deactivate and degrade several NF-kB signaling molecules, such as the receptor interacting protein-1 (RIP1) and TNF receptor-associated factor (TRAF) [6]

Methods

Discussion

Conclusion