Macrophage-Specific MCPIP1/Regnase-1 Attenuates Kidney Ischemia-Reperfusion Injury by Shaping the Local Inflammatory Response and Tissue Regeneration

Abstract

Sterile inflammation either resolves the initial insult or leads to tissue damage. Kidney ischemia/reperfusion injury (IRI) is associated with neutrophilic infiltration, enhanced production of inflammatory mediators, accumulation of necrotic cells and tissue remodeling. Macrophage-dependent microenvironmental changes orchestrate many features of the immune response and tissue regeneration. The activation status of macrophages is influenced by extracellular signals, the duration and intensity of the stimulation, as well as various regulatory molecules. The role of macrophage-derived monocyte chemoattractant protein-induced protein 1 (MCPIP1), also known as Regnase-1, in kidney ischemia-reperfusion injury (IRI) and recovery from sterile inflammation remains unresolved. In this study, we showed that macrophage-specific Mcpip1 deletion significantly affects the kidney phenotype. Macrophage-specific Mcpip1 transgenic mice displayed enhanced inflammation and loss of the tubular compartment upon IRI. We showed that MCPIP1 modulates sterile inflammation by negative regulation of Irf4 expression and accumulation of IRF4+ cells in the tissue and, consequently, suppresses the post-ischemic kidney immune response. Thus, we identified MCPIP1 as an important molecular sentinel of immune homeostasis in experimental acute kidney injury (AKI) and renal fibrosis.

Uremic Toxin Indoxyl Sulfate Promotes Macrophage-Associated Low-Grade Inflammation and Epithelial Cell Senescence

“…Inflammation is a crucial aspect of the immune system, and macrophages employ a variety of extra-and intracellular factors to regulate it [32,33,[61][62][63]. This regulation is essential for maintaining stability and constancy in immune responses and tissue regeneration.…”

“…Total RNA was measured using a NanoDrop ND-1000 Spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). For cDNA conversion, we used an equal amount of RNA (500 ng or 1 µg) of total RNA and SuperScript II Reverse Transcriptase according to the manufacturer's instructions and as described previously [32]. To inactivate the reverse transcriptase, samples were incubated again for 5 min at 90 • C. At the end of the process, samples were stored at −20 • C. The quality of total RNA was assessed using UV spectrophotometry (a ratio of absorbance at 260 nm to 280 nm around 2.0 was considered to indicate pure RNA); agarose gel electrophoresis was performed as random sampling, instead of examining every single sample to provide information on the integrity of the RNA.…”

“…Macrophage homeostasis depends on extensive regulatory mechanisms that orchestrate and sequester inflammatory signals [32][33][34][35]. We hypothesized that macrophages cultured with indoxyl sulfate would display dysregulation of homeostatic transcripts under inflammatory conditions and therefore analyzed the expression of molecules that obstruct inflammatory responses.…”

Regnase-1 overexpression as a therapeutic approach of Marfan syndrome

“…In addition, regnase-1 was shown to act as a negative regulator of oxidative stress. 11 Interestingly, cytokines such as IL-1β, TGF-β, and lipopolysaccharides induce the expression of regnase-1. 12 …”

Immune cell signatures and inflammatory mediators: unraveling their genetic impact on chronic kidney disease through Mendelian randomization

“…The genetic landscape of CKD points to an interplay between genetic predisposition and immune dysregulation, with immune system imbalances playing a crucial role in disease susceptibility and progression [ 5 ]. Treatments targeting immune modulation show promise, particularly when initiated early, in delaying the transition to end-stage renal disease.…”