Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state

Abstract

Intravenous Ig is used to treat autoimmune or autoinflammatory disorders, but the mechanism by which it exerts its immunosuppressive activity is not understood completely. To examine the impact of intravenous Ig on macrophages, we compared cytokine production by LPS-activated macrophages in the presence and absence of intravenous Ig. Intravenous Ig treatment induced robust production of IL-10 in response to LPS, relative to LPS stimulation alone, and reduced production of proinflammatory cytokines. This anti-inflammatory, intravenous Ig-induced activation was sustained for 24 h but could only be induced if intravenous Ig were provided within 1 h of LPS stimulation. Intravenous Ig activation led to enhanced and prolonged activation of MAPKs, Erk1/2, p38, and Erk5, and inhibition of each reduced intravenous Ig-induced IL-10 production and suppression of IL-12/23p40. IL-10 production occurred rapidly in response to intravenous Ig + LPS and was sufficient to reduce proinflammatory IL-12/23p40 production in response to LPS. IL-10 induction and reduced IL-12/23p40 production were transcriptionally regulated. IL-10 played a direct role in reducing proinflammatory cytokine production by macrophages treated with intravenous Ig + LPS, as macrophages from mice deficient in the IL-10R β chain or in IL-10 were compromised in their ability to reduce proinflammatory cytokine production. Finally, intraperitoneal injection of intravenous Ig or intravenous Ig + LPS into mice activated macrophages to produce high levels of IL-10 during subsequent or concurrent LPS challenge, respectively. These findings identify IL-10 as a key anti-inflammatory mediator produced by intravenous Ig-treated macrophages and provide insight into a novel mechanism by which intravenous Ig may dampen down inflammatory responses in patients with autoimmune or autoinflammatory diseases.

Intravenous IgG Reduces Pathogenic Autoantibodies, Serum IL-6 Levels, and Disease Severity in Experimental Bullous Pemphigoid Models

“…Previous studies demonstrated that serum IL-10 levels (D'Auria et al, 1999) and the percentages of IL-10Àproducing T cells (Teraki et al, 2001) are significantly higher in BP patients after therapy with the resolution of the disease than before therapy. IVIG has been reported to induce IL-10 in various models of inflammatory disease (Kozicky et al, 2015;Ramakrishna et al, 2011). Although little is known about how IVIG affects the differentiation of IL-10Àproducing cells, our results suggest that IVIG may regulate the inflammatory responses of BP by promoting the increase of IL-10Àproducing cells.…”

Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy

“…IVIG has been demonstrated to modulate the functions of both innate and adaptive immune cells. Thus, IVIG suppresses the activation of various innate cells such as DCs, macrophages, and monocytes, and the secretion of inflammatory cytokines while enhancing anti- inflammatory mediators like IL-10 and IL-1RA 21,[48][49][50][51][52] . The present data demonstrate that IVIG exerts autophagy in several inflammatory innate cells like monocytes, DCs and M1 macrophages but not in the cells associated with Th2 immune response like M2 macrophages.…”

Macrophage polarization in response to epigenetic modifiers during infection and inflammation

“…Studies have observed that the administration of intravenous immunoglobulin led macrophages to secrete increasing amounts of anti-inflammatory interleukin 10 (IL10). However, this works only if the intravenous immunoglobulin is administered 1 h after the inflammatory attack, and the effect only lasts for 24 h [10]. Thus, there is a dire need to find a more permanent solution to this uncontrolled inflammation.…”