Loss of IRF2BP2 in Microglia Increases Inflammation and Functional Deficits after Focal Ischemic Brain Injury

Abstract

Ischemic stroke causes neuronal cell death and triggers a cascade of inflammatory signals that contribute to secondary brain damage. Microglia, the brain-resident macrophages that remove dead neurons, play a critical role in the brain’s response to ischemic injury. Our previous studies showed that IRF2 binding protein 2 (IRF2BP2) regulates peripheral macrophage polarization, limits their inflammatory response and reduces susceptibility to atherosclerosis. Here, we show that loss of IRF2BP2 in microglia leads to increased inflammatory cytokine expression in response to lipopolysaccharide challenge and impaired activation of anti-inflammatory markers in response to interleukin-4 (IL4) stimulation. Focal ischemic brain injury of the sensorimotor cortex induced by photothrombosis caused more severe functional deficits in mice with IRF2BP2 ablated in macrophages/microglia, associated with elevated expression of inflammatory cytokines in the brain. These mutant mice had larger infarctions 4 days after stroke associated with fewer anti-inflammatory M2 microglia/macrophages recruited to the peri-infarct area, suggesting an impaired clearance of injured tissues. Since IRF2BP2 modulates interferon signaling, and interferon beta (IFNβ) has been reported to be anti-inflammatory and reduce ischemic brain injury, we asked whether loss of IRF2BP2 in macrophages/microglia would affect the response to IFNβ in our stroke model. IFNβ suppressed inflammatory cytokine production of macrophages and reduced infarct volumes at 4 days after photothrombosis in wild type mice. The anti-inflammatory effect of IFNβ was lost in IRF2BP2-deficient macrophages and IFNβ failed to protect mice lacking IRF2BP2 in macrophages/microglia from ischemic injury. In summary, IRF2BP2 expression in macrophages/microglia is important to limit inflammation and stroke injury, in part by mediating the beneficial effect of IFNβ.

IRF2BP2: A new player in the regulation of cell homeostasis

“…Interestingly, stroke recovery occurs via IFN‐β, and the other repressors of the IRF2BP family (IRF2BP1 and IRF2BPL) are not able to compensate for IRF2BP2 deficiency. 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 …”

“…They observed a worsening of atherosclerosis, and IRF2BP2 promoted an anti‐inflammatory M2 profile in macrophages . In a recent work from the same group, the loss of IRF2BP2 in the microglia caused an increased production of inflammatory cytokines . On the other hand, restoring IRF2BP2 expression reduced inflammation and, consequently, decreased the risk of coronary artery disease and stroke .…”

“…In multiple myeloma, the chromosomal aberration of the most common translocation (q13;q32) found in the early stage of pathogenesis contains the IRF2BP2 gene. Having high penetrance (75%), IRF2BP2 might be a potential prognostic marker and therapeutic target in the treatment and management of multiple myeloma patients with this translocation .…”

“…On the other hand, restoring IRF2BP2 expression reduced inflammation and, consequently, decreased the risk of coronary artery disease and stroke . This phenotype is mediated by the effect of IFN‐β …”

“…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.…”