Heterogenous Role of IRF4 in Kidney Fibrosis

A recent article by Sasaki et al.¹ entitled “Deletion of Myeloid Interferon Regulatory Factor 4 (IRF4) in Mouse Model Protects against Kidney Fibrosis after Ischemic Injury by Decreased Macrophage Recruitment and Activation” discussed the role of IRF4 in regulating macrophages during kidney fibrosis. They demonstrated that IRF4 expressed in myeloid cells could promote the development of tubulointerstitial fibrosis after ischemic reperfusion injury (IRI), possibly by orchestrating AKT-mediated monocyte recruitment to the injured kidney. However, Lassen et al.² demonstrated that IRF4 could suppress postischemic inflammation and prevent ARF, as evidenced by the aggravation of inflammatory cytokines and elevated serum creatinine and albumin in IRF4-deficient mice with IRI. Lorenz et al.³ also delineated that IRF4 restricted CKD progression and kidney fibrosis after IRI, potentially by contributing to M2 macrophage polarization and inhibiting T helper 1 cell cytokine responses. Therefore, we have to wonder what is IRF4’s role in kidney fibrosis after IRI?

The authors offered one hypothesis to explain this paradox: IRF4 expressed in different cell types may have different functions in response to acute injury, because IRF4 is also expressed in lymphocytes, including T and B lymphocytes, and IRF4 in T helper 17 cells could regulate anti-inflammatory IL-10 transcription. The authors did not seem to consider that there are far more infiltrating myeloid cells than infiltrating lymphocytes. Thus, the role of IRF4 in kidney fibrosis after IRI might depend mainly on its expression in myeloid cells. IRF4 has also been reported to negatively regulate the production of proinflammatory cytokines, including TNF-α and IL-6, by macrophages in response to Toll-like receptor stimulation, indicating IRF4 might promote macrophage activation.⁴

According to these published data, we hypothesize that IRF4 is capable of promoting migration, but also of inhibiting activation of macrophages. Macrophages in MΦ IRF4^−/− mice could not migrate from bone marrow to peripheral blood, or from peripheral blood to injured kidneys. But the kidney-resident macrophages might undergo increased activation in MΦ IRF4^−/− mice. The protection from kidney fibrosis in MΦ IRF4^−/− mice may have resulted mainly from less infiltration of macrophages into injured kidneys. However, in IRF4 germline knockout mice, the inflammatory cells, including myeloid cells and lymphocytes, that reside in the kidney might be secreting more proinflammatory cytokines, such as TNF-α and IL-6, which partially contributes to an increased migration of macrophages. Thus, we suggest that the authors should detect the quantity of macrophages in bone marrow and peripheral blood in MΦ IRF4^−/− mice, and conduct experiments to study the functions of resident macrophages in kidneys after IRI. The authors have illustrated that IRF4 could promote macrophage migration, possibly by activating phosphatidylinositol 3-kinase/AKT signaling. Moreover, searching concrete binding targets and direct downstream molecules of IRF4 could give more solid evidence of IRF4 positively regulating the migration of macrophages. Studying the molecular mechanism of IRF4 in kidney fibrosis after IRI might result in new strategies to treat this refractory kidney disease.

Disclosures

All authors have nothing to disclose.

Funding

None.