GILZ restrains neutrophil activation by inhibiting the MAPK pathway

Abstract

Glucocorticoid-induced leucine zipper (GILZ) exerts anti-inflammatory effects on the immune cells. However, less is known about GILZ function in neutrophils. We aimed to define the specific role of GILZ in basal neutrophil activity during an inflammatory response. GILZ knockdown resulted in a persistent activation state of neutrophils, as evidenced by increased phagocytosis, killing activity, and oxidative burst in GILZ-knockout (KO) neutrophils. This enhanced response caused severe disease in a dinitrobenzene sulfonic acid (DNBS)-induced colitis model, where GILZ-KO mice had prominent granulocytic infiltrate and excessive inflammatory state. We used a Candida albicans intraperitoneal infection model to unravel the intracellular pathways affected by GILZ expression in activated neutrophils. GILZ-KO neutrophils had stronger ability to clear the infectious agent than the wild-type (WT) neutrophils, and there was more activation of the NOX2 (NADPH oxidase 2) and p47 phox proteins, which are directly involved in oxidative burst. Similarly, the MAPK pathway components, that is, ERK and p38, which are involved in the oxidative burst pathway, were highly phosphorylated in GILZ-KO neutrophils. Evaluation of GILZ expression kinetics during C. albicans infection revealed down-regulation that correlated inversely with the state of neutrophil activation, which was evaluated as oxidative burst. Overall, our findings define GILZ as a regulator of neutrophil functions, as its expression contributes to limiting neutrophil activation by reducing the activation of the signaling pathways that control the basal neutrophil functions. Controlling GILZ expression could help regulate a continuous inflammatory state that can result in chronic inflammatory and autoimmune diseases.

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

“…Hence, corticosteroids have proinflammatory effects in neutrophils. Corticosteroids are generally thought to weakly suppress neutrophilic inflammation, although several research groups reported them to inhibit the neutrophil respiratory burst and interfere with neutrophil recruitment ( Strausbaugh and Rosen, 2001 ; Ronchetti et al, 2018 ; Ricci et al, 2019 ). For instance, corticosteroids do not improve neutrophilic inflammation in corticosteroid-resistant asthma or COPD ( Yang et al, 2012 ; Ronchetti et al, 2018 ).…”

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

“…Its interactions with signal transduction pathways, many of which are operative in RA and other inflammatory diseases, suggest that it is a key endogenous regulator of the immune response including a key glucocorticoid-induced regulator of inflammation in rheumatoid arthritis (RA) (Beaulieu and Morand, 2011). GILTZ is a small, 135-amino acid protein with anti-inflammatory properties and has been shown to inhibit NF-κB and MAPK pathways (Bereshchenko et al, 2019;Ricci et al, 2019). It has also been shown to be induced in response to hypoxia by a HIF1α-dependent mechanism and in response to cholesterol starvation, leading to downstream shedding of procoagulant EVs in ovarian cancer (Koizume et al, 2019).…”

Long Term Delta-9-tetrahydrocannabinol Administration Inhibits Proinflammatory Responses in Minor Salivary Glands of Chronically Simian Immunodeficieny Virus Infected Rhesus Macaques

“…Out of these, 256 and 200 genes were successfully annotated in the VEH-untreated/SIV and THC/SIV groups, respectively. At least five genes with well-established functions in maintaining oral epithelial barrier integrity AGR2 [ 58 , 59 ], WFDC2 [ 60 , 61 ], anti-inflammatory function ( TSC22D3 ) [ 62 , 63 , 64 ] and prevention of oxidative stress [ 48 , 65 ] were found to be significantly downregulated in OPM of VEH-untreated/SIV rhesus macaques ( Figure 1 D). On the other hand, proinflammatory extracellular matrix degrading proteinases ( MMP7 ) [ 66 ], endoplasmic reticulum (ER) stress regulating and anti-viral CREB3L1 [ 67 ] and DNA demethylating APOBEC2 [ 68 ] were significantly downregulated in OPM of THC/SIV rhesus macaques ( Figure 1 D).…”

“…Further, WFDC2 is expressed by MiSGs [ 60 , 61 ] and in association with other related WAP domain containing proteins functions in epithelial host defense. Finally, the expression of TSC22D3 , also known as glucocorticoid induced leucine zipper ( GILZ ), is stimulated by glucocorticoids and IL10 and is well described to play a key role in mediating the anti-inflammatory and immunosuppressive effects of both proteins [ 62 , 63 , 64 ].…”