IRF5 controls both acute and chronic inflammation

Abstract

Whereas the importance of macrophages in chronic inflammatory diseases is well recognized, there is an increasing awareness that neutrophils may also play an important role. In addition to the well-documented heterogeneity of macrophage phenotypes and functions, neutrophils also show remarkable phenotypic diversity among tissues. Understanding the molecular pathways that control this heterogeneity should provide abundant scope for the generation of more specific and effective therapeutics. We have shown that the transcription factor IFN regulatory factor 5 (IRF5) polarizes macrophages toward an inflammatory phenotype. IRF5 is also expressed in other myeloid cells, including neutrophils, where it was linked to neutrophil function. In this study we explored the role of IRF5 in models of acute inflammation, including antigen-induced inflammatory arthritis and lung injury, both involving an extensive influx of neutrophils. Mice lacking IRF5 accumulate far fewer neutrophils at the site of inflammation due to the reduced levels of chemokines important for neutrophil recruitment, such as the chemokine (C-X-C motif) ligand 1. Furthermore we found that neutrophils express little IRF5 in the joints and that their migratory properties are not affected by the IRF5 deficiency. These studies extend prior ones suggesting that inhibiting IRF5 might be useful for chronic macrophage-induced inflammation and suggest that IRF5 blockade would ameliorate more acute forms of inflammation, including lung injury.macrophages | neutrophils | IRF5 | acute inflammation | arthritis

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

“…IRF5 has emerged as a master regulator of the proinflammatory polarization of macrophages (50) and has also been implicated in promoting acute and chronic inflammatory conditions in the lung (51). Furthermore, IRF5 is overactivated in bleomycin-induced skin and lung fibrogenesis, whereas genetic deletion of IRF5 mitigates these conditions (34).…”

Macrophage in chronic kidney disease

“…LPS/IFN-γ-activated M1 macrophages induce renal fibrosis by secretion of MMP-9, which increase tubular cell ECM transition via the β-catenin pathway [5]. The transcription factor IRF5 also seems to play a key role in M1 macrophage polarization, suggesting that inhibiting IRF5 might be useful for chronic macrophage-induced inflammation [40]. …”

An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway

“…These indicate that IRF5 is involved in the development of systemic inflammatory responses. There are some experimental clues to support IRF5 as a central regulator in the TLR signaling pathway: (1) When IRF5 is deficient, TLRs (TLR7/9, TLR4, TLR5) are not able to mediate inflammatory responses (4); (2) IRF5-deficient mice resist lethal shock induced by CpG ODN (TLR9 agonist) or lipopolysaccharide (LPS) (TLR4 agonist) (4); (3) individuals with IRF5 dysregulation may develop autoinflammatory diseases (10); (4) in CAL-1 cells, plasmacytoid-like dendritic cell (pDC) line cells, inhibiting IRF5 expression, significantly reduce mRNA expression of IFN-α and IL-6 (7); and (5) IRF5-/-mice have a significantly reduced number of neutrophils recruited into the lung post LPS challenge and reduced acute lung injury (11). These studies demonstrate that blockade of IRF5 might be an effective method for downregulating production of inflammatory cytokines and therefore ameliorating acute inflammation.…”