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Interferon regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, and has a key pathogenic function in gut inflammation, but how IRF5 is modulated is still unclear. Having performed a kinase inhibitor library screening in macrophages, here we identify protein-tyrosine kinase 2-beta (PTK2B/PYK2) as a putative IRF5 kinase. PYK2-deficient macrophages display impaired endogenous IRF5 activation, leading to reduction of inflammatory gene expression. Meanwhile, a PYK2 inhibitor, defactinib, has a similar effect on IRF5 activation in vitro, and induces a transcriptomic signature in macrophages similar to that caused by IRF5 deficiency. Finally, defactinib reduces pro-inflammatory cytokines in human colon biopsies from patients with ulcerative colitis, as well as in a mouse colitis model. Our results thus implicate a function of PYK2 in regulating the inflammatory response in the gut via the IRF5 innate sensing pathway, thereby opening opportunities for related therapeutic interventions for inflammatory bowel diseases and other inflammatory conditions., (© 2021. The Author(s).)

Interferon regulatory factor 5 (IRF5) is a key signal-dependent transcription factor in myeloid cells. Its expression is induced by granulocyte-macrophage colony stimulating factor and interferon-gamma. IRF5 protein is further activated in response to stimulation, translocating to the nucleus where it mediates inflammatory responses. IRF5 is capable of both the up-regulation of pro-inflammatory genes and repressing anti-inflammatory mediators, thus polarising macrophages to a pro-inflammatory phenotype. We discuss IRF5 interactions with a wide range of transcriptional regulators that give rise to its diverse effects at the level of chromatin., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions., Methods: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE -/- ) mice and ApoE -/- mice with a genetic deletion of IRF5 (ApoE -/- Irf5 -/- ) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation., Results: Both lesion and necrotic core size were significantly reduced in ApoE -/- Irf5 -/- mice compared with IRF5-competent ApoE -/- mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c + macrophages was evident in ApoE -/- Irf5 -/- mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c + macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c - macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ., Conclusions: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c + macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis., (© 2017 The Authors.)