Type I Interferon Modulates Monocyte Recruitment and Maturation in Chronic Inflammation

Abstract

Chronic inflammation is characterized by continuous recruitment and activation of immune cells such as monocytes in response to a persistent stimulus. Production of proinflammatory mediators by monocytes leads to tissue damage and perpetuates the inflammatory response. However, the mechanism(s) responsible for the sustained influx of monocytes in chronic inflammation are not well defined. In chronic peritonitis induced by pristane, the persistent recruitment of Ly6C hi inflammatory monocytes into the peritoneum was abolished in type I interferon (IFN-I) receptor-deficient mice but was unaffected by the absence of IFN-␥, tumor necrosis factor-␣, interleukin-6, or interleukin-1. IFN-I signaling stimulated the production of chemokines (CCL2, CCL7, and CCL12) that recruited Ly6C hi monocytes via interactions with the chemokine receptor CCR2. Interestingly, after 2,6,10,14-tetramethylpentadecane treatment, the rapid turnover of inflammatory monocytes in the inflamed peritoneum was associated with a lack of differentiation into Ly6C lo monocytes/macrophages, a more mature subset with enhanced phagocytic capacity. In contrast, Ly6C hi monocytes differentiated normally into Ly6C lo cells in IFN-I receptor-deficient mice. The effects of IFN-I were specific for monocytes as granulocyte migration was unaffected in the absence of IFN-I signaling. Taken together, our findings reveal a novel role of IFN-I in promoting the recruitment of inflammatory monocytes via the chemokine receptor CCR2. Continuous monocyte recruitment and the lack of terminal differentiation induced by IFN-I may help sustain the chronic inflammatory response.

ATF3 Is a Key Regulator of Macrophage IFN Responses

“…Furthermore, IFN-induced 25-HC was shown to broadly suppress IL-1-activating inflammasomes (63), in line with the known immunosuppressive activity of type I IFNs (3). Consistent with a role in dampening inflammation, we also found that ATF3 regulates the expression of the IFN-inducible chemokines CCL3 and CCL12, which are required for inflammatory monocyte recruitment (64). The overrepresentation of cell surface markers/receptors and chemokines (Supplemental Table II) in addition to Ch25h suggests that ATF3 might be induced by IFN to limit subsequent inflammation and modulate the adaptive immune response.…”

Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue

“…It is known that local type I IFNs are secreted rapidly following HSV-2 infection (19). In addition, type I IFNs have been shown to induce CCR2 ligand expression and recruitment of monocytes (20). Notably, CCR2 ligand production was almost undetectable in the genital mucosa of HSV-2-infected IFN-αβR −/− mice (Fig.…”

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

“…It is induced by donor T cells and inflammatory cytokines causing damage to host epithelial tissues, predominantly the skin, liver and gastrointestinal tract. [1][2][3] Despite pharmacological prophylaxis, about half of the patients receiving allogeneic hematopoietic stem cell transplantation experience severe aGVHD, which requires high-dose steroid treatment and often has a highly unsatisfactory outcome. Therefore, an immunomodulatory regimen is urgently needed for aGVHD prevention and treatment.…”

“…[4][5][6][7] S1P is mainly produced by erythrocytes and endothelial cells. S1P binds to five known G protein-coupled receptors, S1P [1][2][3][4][5] , and acts as a second messenger during cell signaling. 8,9 Most S1P-dependent immune modulations were discovered using the receptor agonist FTY720.…”