IRF2BP2-deficient microglia block the anxiolytic effect of enhanced postnatal care

Abstract

Enhanced postnatal care (EPC) increases resilience to adversity in adulthood. Since microglia participate in shaping neural circuits, we asked how ablation of an inflammation-suppressing factor IRF2BP2 (Interferon Regulatory Factor 2 Binding Protein 2) in microglia would affect the responses to EPC. Mice lacking IRF2BP2 in microglia (KO) and littermate controls (WT) were subjected to EPC during the first 3 weeks after birth. EPC reduced anxiety in WT but not KO mice. This was associated with reduced inflammatory cytokine expression in the hypothalamus. Whole genome RNAseq profiling of the hypothalamus identified 101 genes whose expression was altered by EPC: 95 in WT, 11 in KO, with 5 in common that changed in opposite directions. Proteoglycan 4 (Prg4), prostaglandin D2 synthase (Ptgds) and extracellular matrix protease inhibitor Itih2 were suppressed by EPC in WT but elevated in KO mice. On the other hand, the glutamate transporter VGLUT1 (Slc17a7) was increased by EPC in WT but not KO mice. Prostaglandin D2 (PGD2) is known to enhance microglial inflammation and promote Gfap expression. ELISA confirmed reduced PGD2 in the hypothalamus of WT mice after EPC, associated with reduced Gfap expression. Our study suggests that the anxiety-reducing effect of EPC operates by suppressing microglial inflammation, likely by reducing neuronal prostaglandin D2 production.

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

“…IRF2BP2‐deficient macrophages showed enhanced inflammatory phenotype and worsened atherosclerosis in mice . Similarly, loss of IRF2BP2 in microglia, the brain‐resident macrophages, leads to an enhanced inflammatory phenotype . In addition, a gain‐of‐function mutation of IRF2BP2 is proposed as a cause for a familial form of common variable immunodeficiency disorder .…”

Transient deSUMOylation of IRF2BP proteins controls early transcription in EGFR signaling

“…More recently, the IRF2BP proteins have emerged as important factors in the immune system. They can suppress inflammation in macrophages and microglia (Chen et al, 2015;Cruz et al, 2017;Hari et al, 2017) and have inhibitory effects on the expression of the programmed death ligand 1 (PD-L1) (Dorand et al, 2016;Soliman et al, 2014;Wu et al, 2019). Furthermore, IRF2BP2 was found to regulate the Hippo pathway in liver cancer and to act as a tumor suppressor (Feng et al, 2019).…”

IRF2BP2: A new player in the regulation of cell homeostasis

“…These data suggest a specific function for IRF2BP2 in IFN‐β signaling . In addition, the same group demonstrated that IRF2BP2 in microglia is necessary for the anxiety‐reducing effect of enhanced maternal care by suppressing IL‐1β expression in mice …”

“…11 In addition, the same group demonstrated that IRF2BP2 in microglia is necessary for the anxiety-reducing effect of enhanced maternal care by suppressing IL-1 expression in mice. 12 It is important to highlight the study performed by Arruda and colleagues 16 that reported that multiple sclerosis is characterized by high levels of microRNA associated with low levels of IRF2BP2.…”

“…4 Some studies have suggested that IRF2BP2 is involved in angiogenesis during cancer development, 5 DNA repair, 2 gene fusion, [6][7][8] and immune system evasion. 9 Furthermore, it has been recently reported that IRF2BP2 has a role in macrophage regulation [10][11][12] and lymphocyte activation, 13,14 highlighting its function in the innate and adaptive immune responses.…”