IRF5 Is a Key Regulator of Macrophage Response to Lipopolysaccharide in Newborns

Abstract

Infections are a leading cause of mortality and morbidity in newborns. The high susceptibility of newborns to infection has been associated with a limited capacity to mount protective immune responses. Monocytes and macrophages are involved in the initiation, amplification, and termination of immune responses. Depending on cues received from their environment, monocytes differentiate into M1 or M2 macrophages with proinflammatory or anti-inflammatory and tissue repair properties, respectively. The purpose of this study was to characterize differences in monocyte to macrophage differentiation and polarization between newborns and adults. Monocytes from umbilical cord blood of healthy term newborns and from peripheral blood of adult healthy subjects were exposed to GM-CSF or M-CSF to induce M1 or M2 macrophages. Newborn monocytes differentiated into M1 and M2 macrophages with similar morphology and expression of differentiation/polarization markers as adult monocytes, with the exception of CD163 that was expressed at sevenfold higher levels in newborn compared to adult M1 macrophages. Upon TLR4 stimulation, newborn M1 macrophages produced threefold to sixfold lower levels of TNF than adult macrophages, while production of IL-1-β, IL-6, IL-8, IL-10, and IL-23 was at similar levels as in adults. Nuclear levels of IRF5, a transcription factor involved in M1 polarization, were markedly reduced in newborns, whereas the NF-κB and MAP kinase pathways were not altered. In line with a functional role for IRF5, adenoviral-mediated IRF5 overexpression in newborn M1 macrophages restored lipopolysaccharide-induced TNF production. Altogether, these data highlight a distinct immune response of newborn macrophages and identify IRF5 as a key regulator of macrophage TNF response in newborns.

Increased Adipose Tissue Expression of Interferon Regulatory Factor (IRF)-5 in Obesity: Association with Metabolic Inflammation

“…Our data also show a positive association of the adipose IRF5 gene expression with that of chemokine receptors such as CCR1, CCR2, and CCR5. Consistent with these data, IRF5 expression was found to be associated with various inflammatory markers [36,37,38,39,40,41,42]. However, we also noted discordance between gene and protein expression of CCL2 and CCL5 in the adipose tissue which may be due to variability in the stabilities of their mRNAs and proteins in the adipose tissue in obesity.…”

Myeloid cell IRF4 signaling protects neonatal brains from hypoxic ischemic encephalopathy

“…Studies of peripheral inflammation suggested that the activation of monocytes is mediated either by IRF4 augmentation of M2 (anti-inflammatory) polarization, or by IRF5 towards M1 phenotype. However, IRF4 signaling in these studies functioned through both anti-and pro-inflammatory pathways (Gunthner and Anders, 2013;Satoh et al, 2010;Schneider et al, 2018). Cytoplasmic IRF4 can not only translocate to the nucleus to mediate expression of anti-inflammatory mediators, but can also compete with IRF5 to bind to the adaptor protein MyD88 to reduce IRF5 phosphorylation leading to suppression of M1 activation (Marecki et al, 1999;Negishi et al, 2005).…”

Sirtuin 5 Deficiency Does Not Compromise Innate Immune Responses to Bacterial Infections

“…Blots were imaged with the ECL Western blotting system (GE Healthcare, Little Chalfont, UK). Images were recorded using a Fusion Fx system (Viber Lourmat, Collégien, France) ( 36 ).…”